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Roles of Cardiovascular Active Substances and Cellular Events in the Homeostasis of Cardiovascular Systems 2018

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2019) | Viewed by 77559

Special Issue Editors

Prof. Dr. Hideyuki Yamawaki

E-Mail Website
Guest Editor
Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 bancho 35–1, Towada, Aomori 034–8628, Japan
Interests: vascular biology; hypertension; atherosclerosis; adipocytokine; diabetes-related vascular dysfunction; hypertrophy; heart failure; pulmonary arterial hypertension; calmodulin-related proteins; cardiovascular pharmacology
Special Issues, Collections and Topics in MDPI journals
Dr. Takayuki Matsumoto

E-Mail Website
Guest Editor
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
Interests: vascular biology; endothelial dysfunction; endothelium-derived factors; diabetes; hypertension; vascular smooth muscle; chronic inflammation; oxidative stress; endoplasmic reticulum stress; aging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cardiovascular active substances contribute to the maintenance of cardiovascular homeostasis. Conversely, disturbances might potentially induce cardiovascular diseases (CVDs). For example, continuous production of endothelium-derived substances, including nitric oxide and vasodilating prostanoids, is protective against CVDs, such as hypertension, atherosclerosis, and ischemic CVDs, while the increased production of endithelium-derived substances, including constrictive prostanoids and endothelin-1, potentially promote CVDs. Thus, the balance of cardiovascular active substances is very important for the maintenance of cardiovascular homeostasis. In addition to such classical substances, many other novel cardiovascular active substances, such as adipocyte-derived cytokine (adipocytokine) and matricryptins (active fragments of extracellular matrix), have been identified. Moreover, cellular events, including endoplasmic reticulum stress, mitochondrial dysfunction, and apoptosis induced by the abovementioned substances or inflammation, also play important roles in the development of CVDs. In this Special Issue, we aim at collecting current knowledge of those cardiovascular active substances and cellular events, summarize their mechanisms of actions, on both cardiovascular physiology and pathophysiology, and explore their potential applications in the treatment and diagnosis of CVDs.

Prof. Dr. Hideyuki Yamawaki
Dr. Takayuki Matsumoto
Guest Editors

Manuscript Submission Information

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Keywords

  • hypertension
  • atherosclerosis
  • diabetes-related cardiovascular diseases
  • pulmonary arterial hypertension
  • ischemic cardiovascular diseases
  • cardiac hypertrophy/failure
  • endothelium
  • vascular smooth muscle
  • cardiac cells
  • adipocytokine
  • extracellular matrix
  • endoplasmic reticulum stress
  • mitochondrial dysfunction
  • gestational hypertension
  • chronic inflammation

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Published Papers (15 papers)

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Research

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16 pages, 4126 KiB  
Article
Role of Neuron–Glia Signaling in Regulation of Retinal Vascular Tone in Rats
by Eriko Someya, Mari Akagawa, Asami Mori, Akane Morita, Natsuko Yui, Daiki Asano, Kenji Sakamoto and Tsutomu Nakahara
Int. J. Mol. Sci. 2019, 20(8), 1952; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20081952 - 20 Apr 2019
Cited by 9 | Viewed by 2755
Abstract
The interactions between neuronal, glial, and vascular cells play a key role in regulating blood flow in the retina. In the present study, we examined the role of the interactions between neuronal and glial cells in regulating the retinal vascular tone in rats [...] Read more.
The interactions between neuronal, glial, and vascular cells play a key role in regulating blood flow in the retina. In the present study, we examined the role of the interactions between neuronal and glial cells in regulating the retinal vascular tone in rats upon stimulation of retinal neuronal cells by intravitreal injection of N-methyl-d-aspartic acid (NMDA). The retinal vascular response was assessed by measuring the diameter of the retinal arterioles in the in vivo fundus images. Intravitreal injection of NMDA produced retinal vasodilation that was significantly diminished following the pharmacological inhibition of nitric oxide (NO) synthase (nNOS), loss of inner retinal neurons, or intravitreal injection of glial toxins. Immunohistochemistry revealed the expression of nNOS in ganglion and calretinin-positive amacrine cells. Moreover, glial toxins significantly prevented the retinal vasodilator response induced by intravitreal injection of NOR3, an NO donor. Mechanistic analysis revealed that NO enhanced the production of vasodilatory prostanoids and epoxyeicosatrienoic acids in glial cells in a ryanodine receptor type 1-dependent manner, subsequently inducing the retinal vasodilator response. These results suggest that the NO released from stimulated neuronal cells acts as a key messenger in neuron–glia signaling, thereby causing neuronal activity-dependent and glial cell-mediated vasodilation in the retina. Full article
(This article belongs to the Special Issue Roles of Cardiovascular Active Substances and Cellular Events in the Homeostasis of Cardiovascular Systems 2018)
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16 pages, 3022 KiB  
Article
Angiotensin II Induces Automatic Activity of the Isolated Guinea Pig Pulmonary Vein Myocardium through Activation of the IP3 Receptor and the Na+-Ca2+ Exchanger
by Yusuke Tanaka, Kae Obata, Tamano Ohmori, Kohei Ishiwata, Manato Abe, Shogo Hamaguchi, Iyuki Namekata and Hikaru Tanaka
Int. J. Mol. Sci. 2019, 20(7), 1768; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20071768 - 10 Apr 2019
Cited by 10 | Viewed by 2707
Abstract
The automaticity of the pulmonary vein myocardium is known to be the major cause of atrial fibrillation. We examined the involvement of angiotensin II in the automatic activity of isolated guinea pig pulmonary vein preparations. In tissue preparations, application of angiotensin II induced [...] Read more.
The automaticity of the pulmonary vein myocardium is known to be the major cause of atrial fibrillation. We examined the involvement of angiotensin II in the automatic activity of isolated guinea pig pulmonary vein preparations. In tissue preparations, application of angiotensin II induced an automatic contractile activity; this effect was mimicked by angiotensin I and blocked by losartan, but not by PD123,319 or carvedilol. In cardiomyocytes, application of angiotensin II induced an increase in the frequency of spontaneous Ca2+ sparks and the generation of Ca2+ transients; these effects were inhibited by losartan or xestospongin C. In tissue preparations, angiotensin II caused membrane potential oscillations, which lead to repetitive generation of action potentials. Angiotensin II increased the diastolic depolarization slope of the spontaneous or evoked action potentials. These effects of angiotensin II were inhibited by SEA0400. In tissue preparations showing spontaneous firing of action potentials, losartan, xestospongin C or SEA0400 decreased the slope of the diastolic depolarization and inhibited the firing of action potentials. In conclusion, in the guinea pig pulmonary vein myocardium, angiotensin II induces the generation of automatic activity through activation of the IP3 receptor and the Na+-Ca2+ exchanger. Full article
(This article belongs to the Special Issue Roles of Cardiovascular Active Substances and Cellular Events in the Homeostasis of Cardiovascular Systems 2018)
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14 pages, 2677 KiB  
Article
Acute Exposure to Indoxyl Sulfate Impairs Endothelium-Dependent Vasorelaxation in Rat Aorta
by Takayuki Matsumoto, Keisuke Takayanagi, Mihoka Kojima, Kumiko Taguchi and Tsuneo Kobayashi
Int. J. Mol. Sci. 2019, 20(2), 338; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20020338 - 15 Jan 2019
Cited by 23 | Viewed by 3815
Abstract
Gut microbiota are emerging as potential contributors to the regulation of host homeostasis. Dysbiosis of the gut microbiota associated with increased intestinal permeability facilitates the passage of endotoxins and other microbial products, including indoxyl sulfate in the circulation. Although an emerging body of [...] Read more.
Gut microbiota are emerging as potential contributors to the regulation of host homeostasis. Dysbiosis of the gut microbiota associated with increased intestinal permeability facilitates the passage of endotoxins and other microbial products, including indoxyl sulfate in the circulation. Although an emerging body of evidence has suggested that indoxyl sulfate is a key substance for the development of chronic kidney disease, few studies have investigated the direct association of indoxyl sulfate with vascular function. We hypothesized that indoxyl sulfate adversely affects vascular function. Aortas isolated from male Wistar rat were examined in the presence or absence of indoxyl sulfate to assess the vascular function, including vasorelaxation and vasocontraction. Indoxyl sulfate (vs. vehicle) (1) decreased vasorelaxation induced by acetylcholine (ACh) but not by sodium nitroprusside; (2) had no significant alterations of noradrenaline-induced vasocontraction in the absence and presence of endothelium; (3) decreased adenylyl cyclase activator (forskolin)-induced vasorelaxation, while such a difference was eliminated by endothelial denudation; and (4) decreased vasorelaxations induced by calcium ionophore (A23187) and transient receptor potential vanilloid 4 agonist (GSK1016790A). The indoxyl sulfate-induced decrease in the vasorelaxations induced by ACh and A23187 increased by cell-permeant superoxide dismutase or by organic anion transporter inhibitor. However, apocynin, an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, had no effects on vasorelaxations induced by ACh, A23187, forskolin, and GSK1016790A in the presence of indoxyl sulfate. These results suggest that indoxyl sulfate directly affects the vascular function, particularly, endothelium-dependent vasorelaxation, and this effect may be attributable to increased oxidative stress after cell transportion via organic anion transporter, and such increased oxidative stress may not be attributable to activation of NADPH oxidase activation. Full article
(This article belongs to the Special Issue Roles of Cardiovascular Active Substances and Cellular Events in the Homeostasis of Cardiovascular Systems 2018)
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12 pages, 2641 KiB  
Article
Loss of Apelin Augments Angiotensin II-Induced Cardiac Dysfunction and Pathological Remodeling
by Teruki Sato, Ayumi Kadowaki, Takashi Suzuki, Hiroshi Ito, Hiroyuki Watanabe, Yumiko Imai and Keiji Kuba
Int. J. Mol. Sci. 2019, 20(2), 239; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20020239 - 09 Jan 2019
Cited by 41 | Viewed by 4752
Abstract
Apelin is an inotropic and cardioprotective peptide that exhibits beneficial effects through activation of the APJ receptor in the pathology of cardiovascular diseases. Apelin induces the expression of angiotensin-converting enzyme 2 (ACE2) in failing hearts, thereby improving heart function in an angiotensin 1–7-dependent [...] Read more.
Apelin is an inotropic and cardioprotective peptide that exhibits beneficial effects through activation of the APJ receptor in the pathology of cardiovascular diseases. Apelin induces the expression of angiotensin-converting enzyme 2 (ACE2) in failing hearts, thereby improving heart function in an angiotensin 1–7-dependent manner. Whether apelin antagonizes the over-activation of the renin–angiotensin system in the heart remains elusive. In this study we show that the detrimental effects of angiotensin II (Ang II) were exacerbated in the hearts of aged apelin-gene-deficient mice. Ang II-mediated cardiac dysfunction and hypertrophy were augmented in apelin knockout mice. The loss of apelin increased the ratio of angiotensin-converting enzyme (ACE) to ACE2 expression in the Ang II-stressed hearts, and Ang II-induced cardiac fibrosis was markedly enhanced in apelin knockout mice. mRNA expression of pro-fibrotic genes, such as transforming growth-factor beta (TGF-β) signaling, were significantly upregulated in apelin knockout hearts. Consistently, treatment with the ACE-inhibitor Captopril decreased cardiac contractility in apelin knockout mice. In vitro, apelin ameliorated Ang II-induced TGF-β expression in primary cardiomyocytes, accompanied with reduced hypertrophy. These results provide direct evidence that endogenous apelin plays a crucial role in suppressing Ang II-induced cardiac dysfunction and pathological remodeling. Full article
(This article belongs to the Special Issue Roles of Cardiovascular Active Substances and Cellular Events in the Homeostasis of Cardiovascular Systems 2018)
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15 pages, 2396 KiB  
Article
Perivascular Adipose Tissue-Enhanced Vasodilation in Metabolic Syndrome Rats by Apelin and N-Acetyl–l-Cysteine-Sensitive Factor(s)
by Satomi Kagota, Kana Maruyama-Fumoto, Saki Iwata, Miho Shimari, Shiori Koyanagi, Yayoi Shiokawa, John J. McGuire and Kazumasa Shinozuka
Int. J. Mol. Sci. 2019, 20(1), 106; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20010106 - 28 Dec 2018
Cited by 15 | Viewed by 2971
Abstract
Perivascular adipose tissue (PVAT) can regulate vascular tone. In mesenteric arteries of SHRSP.Z-Leprfa/IzmDmcr rats (SHRSP.ZF) with metabolic syndrome, vascular dysfunction is compensated by PVAT-dependent mechanisms that disappear with increasing age. In this study, we investigated the mechanisms of the age-related [...] Read more.
Perivascular adipose tissue (PVAT) can regulate vascular tone. In mesenteric arteries of SHRSP.Z-Leprfa/IzmDmcr rats (SHRSP.ZF) with metabolic syndrome, vascular dysfunction is compensated by PVAT-dependent mechanisms that disappear with increasing age. In this study, we investigated the mechanisms of the age-related changes and responsible factor(s) involved in the enhancing effects of mesenteric arterial PVAT in SHRSP.ZF. Acetylcholine- and sodium nitroprusside-induced relaxations of isolated arteries were greater with PVAT than without PVAT at 17 and 20 weeks of age (wks), and as expected, this enhancement by the presence of PVAT disappeared at 23 wks. PVAT mRNA levels of angiotensin II type 1 (AT1) receptor-associated protein was less and AT1 receptor was unchanged at 23 wks when compared to 20 wks. At 20 wks, the enhanced acetylcholine-induced relaxation by the presence of PVAT was inhibited by N-acetyl-l-cysteine (NAC). Acetylcholine-induced relaxation of arteries without PVAT was increased in the presence of exogenously added apelin. PVAT mRNA level of apelin was higher in SHRSP.ZF than in control Wistar-Kyoto rats, and the level was decreased with aging. These results suggest that AT1 receptor activation in PVAT, and changes in the regulation of apelin and a NAC-sensitive factor are related to the age-dependent deterioration of the vasodilation enhancing effects of mesenteric arterial PVAT in SHRSP.ZF. Full article
(This article belongs to the Special Issue Roles of Cardiovascular Active Substances and Cellular Events in the Homeostasis of Cardiovascular Systems 2018)
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16 pages, 5840 KiB  
Article
Periostin Mediates Right Ventricular Failure through Induction of Inducible Nitric Oxide Synthase Expression in Right Ventricular Fibroblasts from Monocrotaline-Induced Pulmonary Arterial Hypertensive Rats
by Keisuke Imoto, Muneyoshi Okada and Hideyuki Yamawaki
Int. J. Mol. Sci. 2019, 20(1), 62; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20010062 - 24 Dec 2018
Cited by 12 | Viewed by 4484
Abstract
Pulmonary arterial hypertension (PAH) leads to lethal right ventricular failure (RVF). Periostin (POSTN) mRNA expression is increased in right ventricles (RVs) of monocrotaline (MCT)-induced PAH model rats. However, the pathophysiological role of POSTN in RVF has not been clarified. We investigated [...] Read more.
Pulmonary arterial hypertension (PAH) leads to lethal right ventricular failure (RVF). Periostin (POSTN) mRNA expression is increased in right ventricles (RVs) of monocrotaline (MCT)-induced PAH model rats. However, the pathophysiological role of POSTN in RVF has not been clarified. We investigated the effects of POSTN on inducible nitric oxide (NO) synthase (iNOS) expression and NO production, which causes cardiac dysfunction, in right ventricular fibroblasts (RVFbs). Male Wistar rats were intraperitoneally injected with MCT (60 mg/kg) or saline. Three weeks after injection, RVFbs were isolated from RVs of MCT- or saline-injected rats (MCT-RVFb or CONT-RVFb). In MCT-RVFb, iNOS expression and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) were higher than those in CONT-RVFb. Recombinant POSTN increased iNOS expression and NO production, which were prevented by a pharmacological inhibition of ERK1/2, JNK or NF-κB in RVFbs isolated from normal rats. Culture medium of POSTN-stimulated RVFbs suppressed Ca2+ inflow through l-type Ca2+ channel (LTCC) in H9c2 cardiomyoblasts. We demonstrated that POSTN enhances iNOS expression and subsequent NO production via ERK1/2, JNK, and NF-κB signaling pathways in RVFbs. POSTN might mediate RVF through the suppression of LTCC activity of cardiomyocytes by producing NO from RVFbs in PAH model rats. Full article
(This article belongs to the Special Issue Roles of Cardiovascular Active Substances and Cellular Events in the Homeostasis of Cardiovascular Systems 2018)
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14 pages, 1973 KiB  
Article
Altered Purinergic Receptor Sensitivity in Type 2 Diabetes-Associated Endothelial Dysfunction and Up4A-Mediated Vascular Contraction
by Ali Mahdi, Tong Jiao, Yahor Tratsiakovich, Jiangning Yang, Claes-Göran Östenson, John Pernow and Zhichao Zhou
Int. J. Mol. Sci. 2018, 19(12), 3942; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19123942 - 07 Dec 2018
Cited by 14 | Viewed by 3278
Abstract
Purinergic signaling may be altered in diabetes accounting for endothelial dysfunction. Uridine adenosine tetraphosphate (Up4A), a novel dinucleotide substance, regulates vascular function via both purinergic P1 and P2 receptors (PR). Up4A enhances vascular contraction in isolated arteries of diabetic [...] Read more.
Purinergic signaling may be altered in diabetes accounting for endothelial dysfunction. Uridine adenosine tetraphosphate (Up4A), a novel dinucleotide substance, regulates vascular function via both purinergic P1 and P2 receptors (PR). Up4A enhances vascular contraction in isolated arteries of diabetic rats likely through P2R. However, the precise involvement of PRs in endothelial dysfunction and the vasoconstrictor response to Up4A in diabetes has not been fully elucidated. We tested whether inhibition of PRs improved endothelial function and attenuated Up4A-mediated vascular contraction using both aortas and mesenteric arteries of type 2 diabetic (T2D) Goto Kakizaki (GK) rats vs. control Wistar (WT) rats. Endothelium-dependent (EDR) but not endothelium-independent relaxation was significantly impaired in both aortas and mesenteric arteries from GK vs. WT rats. Non-selective inhibition of P1R or P2R significantly improved EDR in aortas but not mesenteric arteries from GK rats. Inhibition of A1R, P2X7R, or P2Y6R significantly improved EDR in aortas. Vasoconstrictor response to Up4A was enhanced in aortas but not mesenteric arteries of GK vs. WT rats via involvement of A1R and P2X7R but not P2Y6R. Depletion of major endothelial component nitric oxide enhanced Up4A-induced aortic contraction to a similar extent between WT and GK rats. No significant differences in protein levels of A1R, P2X7R, and P2Y6R in aortas from GK and WT rats were observed. These data suggest that altered PR sensitivity accounts for endothelial dysfunction in aortas in diabetes. Modulating PRs may represent a potential therapy for improving endothelial function. Full article
(This article belongs to the Special Issue Roles of Cardiovascular Active Substances and Cellular Events in the Homeostasis of Cardiovascular Systems 2018)
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16 pages, 6129 KiB  
Article
Deletion of RasGRF1 Attenuated Interstitial Fibrosis in Streptozotocin-Induced Diabetic Cardiomyopathy in Mice through Affecting Inflammation and Oxidative Stress
by Tzu-Hsien Tsai, Cheng-Jei Lin, Sarah Chua, Sheng-Ying Chung, Shyh-Ming Chen, Chien-Ho Lee and Chi-Ling Hang
Int. J. Mol. Sci. 2018, 19(10), 3094; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19103094 - 10 Oct 2018
Cited by 13 | Viewed by 3385
Abstract
Background: Diabetic cardiomyopathy (DCM) is characterized by cardiac fibrosis and stiffness, which often develops into heart failure. This study investigated the role of Ras protein-specific guanine nucleotide releasing factor 1 (RasGRF1) in the development of DCM. Methods: Forty-eight mice were divided into four [...] Read more.
Background: Diabetic cardiomyopathy (DCM) is characterized by cardiac fibrosis and stiffness, which often develops into heart failure. This study investigated the role of Ras protein-specific guanine nucleotide releasing factor 1 (RasGRF1) in the development of DCM. Methods: Forty-eight mice were divided into four groups (n = 12 per group): Group 1: Wild-type (WT) mice, Group 2: RasGRF1 deficiency (RasGRF1−/−) mice. Group 3: Streptozotocin (STZ)-induced diabetic WT mice, Group 4: STZ-induced diabetic RasGRF1−/− mice. Myocardial functions were assessed by cardiac echography. Heart tissues from all of the mice were investigated for cardiac fibrosis, inflammation, and oxidative stress markers. Results: Worse impaired diastolic function with elevation serum interleukin (IL)-6 was found in the diabetic group compared with the non-diabetic groups. Serum IL-6 levels were found to be elevated in the diabetic compared with the non-diabetic groups. However, the diabetic RasGRF1−/− mice exhibited lower serum IL-6 levels and better diastolic function than the diabetic WT mice. The diabetic RasGRF1−/− mice were associated with reduced cardiac inflammation, which was shown by lower invading inflammation cells, lower expression of matrix metalloproteinase 9, and less chemokines compared to the diabetic WT mice. Furthermore, less oxidative stress as well as extracellular matrix deposition leading to a reduction in cardiac fibrosis was also found in the diabetic RasGRF1−/− mice compared with the diabetic WT mice. Conclusion: The deletion of RasGRF1 attenuated myocardial fibrosis and improved cardiac function in diabetic mice through inhibiting inflammation and oxidative stress. Full article
(This article belongs to the Special Issue Roles of Cardiovascular Active Substances and Cellular Events in the Homeostasis of Cardiovascular Systems 2018)
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15 pages, 3292 KiB  
Article
Effect of Ivabradine on a Hypertensive Heart and the Renin-Angiotensin-Aldosterone System in L-NAME-Induced Hypertension
by Fedor Simko, Tomas Baka, Marko Poglitsch, Kristina Repova, Silvia Aziriova, Kristina Krajcirovicova, Stefan Zorad, Michaela Adamcova and Ludovit Paulis
Int. J. Mol. Sci. 2018, 19(10), 3017; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19103017 - 03 Oct 2018
Cited by 28 | Viewed by 4635
Abstract
Ivabradine, the selective inhibitor of the If current in the sinoatrial node, exerts cardiovascular protection by its bradycardic effect and potentially pleiotropic actions. However, there is a shortage of data regarding ivabradine’s interaction with the renin-angiotensin-aldosterone system (RAAS). This study investigated whether ivabradine [...] Read more.
Ivabradine, the selective inhibitor of the If current in the sinoatrial node, exerts cardiovascular protection by its bradycardic effect and potentially pleiotropic actions. However, there is a shortage of data regarding ivabradine’s interaction with the renin-angiotensin-aldosterone system (RAAS). This study investigated whether ivabradine is able to protect a hypertensive heart in the model of L-NAME-induced hypertension and to interfere with the RAAS. Four groups (n = 10/group) of adult male Wistar rats were treated as follows for four weeks: control, ivabradine (10 mg/kg/day), L-NAME (40 mg/kg/day), and L-NAME plus ivabradine. L-NAME administration increased systolic blood pressure (SBP) and left ventricular (LV) weight, enhanced hydroxyproline concentration in the LV, and deteriorated the systolic and diastolic LV function. Ivabradine reduced heart rate (HR) and SBP, and improved the LV function. The serum concentrations of angiotensin Ang 1–8 (Ang II), Ang 1–5, Ang 1–7, Ang 1–10, Ang 2–8, and Ang 3–8 were decreased in the L-NAME group and ivabradine did not modify them. The serum concentration of aldosterone and the aldosterone/Ang II ratio were enhanced by L-NAME and ivabradine reduced these changes. We conclude that ivabradine improved the LV function of the hypertensive heart in L-NAME-induced hypertension. The protective effect of ivabradine might have been associated with the reduction of the aldosterone level. Full article
(This article belongs to the Special Issue Roles of Cardiovascular Active Substances and Cellular Events in the Homeostasis of Cardiovascular Systems 2018)
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16 pages, 10071 KiB  
Article
Bradykinin B2 Receptor Contributes to Inflammatory Responses in Human Endothelial Cells by the Transactivation of the Fibroblast Growth Factor Receptor FGFR-1
by Erika Terzuoli, Federico Corti, Ginevra Nannelli, Antonio Giachetti, Sandra Donnini and Marina Ziche
Int. J. Mol. Sci. 2018, 19(9), 2638; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19092638 - 06 Sep 2018
Cited by 17 | Viewed by 5926
Abstract
Elevated levels of bradykinin (BK) and fibroblast growth factor-2 (FGF-2) have been implicated in the pathogenesis of inflammatory and angiogenic disorders. In angiogenesis, both stimuli induce a pro-inflammatory signature in endothelial cells, activating an autocrine/paracrine amplification loop that sustains the neovascularization process. Here [...] Read more.
Elevated levels of bradykinin (BK) and fibroblast growth factor-2 (FGF-2) have been implicated in the pathogenesis of inflammatory and angiogenic disorders. In angiogenesis, both stimuli induce a pro-inflammatory signature in endothelial cells, activating an autocrine/paracrine amplification loop that sustains the neovascularization process. Here we investigated the contribution of the FGF-2 pathway in the BK-mediated human endothelial cell permeability and migration, and the role of the B2 receptor (B2R) of BK in this cross-talk. BK (1 µM) upregulated the FGF-2 expression and promoted the FGF-2 signaling, both in human umbilical vein endothelial cells (HUVEC) and in retinal capillary endothelial cells (HREC) by the activation of Fibroblast growth factor receptor-1 (FGFR-1) and its downstream signaling (fibroblast growth factor receptor substrate: FRSα, extracellular signal–regulated kinases1/2: ERK1/2, and signal transducer and activator of transcription 3: STAT3 phosphorylation). FGFR-1 phosphorylation triggered by BK was c-Src mediated and independent from FGF-2 upregulation. Either HUVEC and HREC exposed to BK showed increased permeability, disassembly of adherens and tight-junction, and increased cell migration. B2R blockade by the selective antagonist, fasitibant, significantly inhibited FGF-2/FGFR-1 signaling, and in turn, BK-mediated endothelial cell permeability and migration. Similarly, the FGFR-1 inhibitor, SU5402, and the knock-down of the receptor prevented the BK/B2R inflammatory response in endothelial cells. In conclusion, this work demonstrates the existence of a BK/B2R/FGFR-1/FGF-2 axis in endothelial cells that might be implicated in propagation of angiogenic/inflammatory responses. A B2R blockade, by abolishing the initial BK stimulus, strongly attenuated FGFR-1-driven cell permeability and migration. Full article
(This article belongs to the Special Issue Roles of Cardiovascular Active Substances and Cellular Events in the Homeostasis of Cardiovascular Systems 2018)
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15 pages, 1303 KiB  
Article
Upregulation of Nrf2 and Decreased Redox Signaling Contribute to Renoprotective Effects of Chemerin Receptor Blockade in Diabetic Mice
by Karla Bianca Neves, Augusto Cesar Montezano, Rheure Alves-Lopes, Thiago Bruder-Nascimento, Rafael Menezes Costa, Roberto S Costa, Rhian M Touyz and Rita C Tostes
Int. J. Mol. Sci. 2018, 19(8), 2454; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19082454 - 19 Aug 2018
Cited by 18 | Viewed by 5364
Abstract
Chemerin, acting through its receptor ChemR23, is an adipokine associated with inflammatory response, glucose and lipid metabolism and vascular function. Although this adipokine has been associated with the development and progression of kidney disease, it is not clear whether the chemerin/ChemR23 system plays [...] Read more.
Chemerin, acting through its receptor ChemR23, is an adipokine associated with inflammatory response, glucose and lipid metabolism and vascular function. Although this adipokine has been associated with the development and progression of kidney disease, it is not clear whether the chemerin/ChemR23 system plays a role in renal function in the context of diabetes. Therefore, we sought to determine whether ChemR23 receptor blockade prevents the development and/or progression of diabetic nephropathy and questioned the role of oxidative stress and Nrf2 in this process. Renal redox state and function were assessed in non-diabetic lean db/m and diabetic obese db/db mice treated with vehicle or CCX832 (ChemR23 antagonist). Renal reactive oxygen species (ROS) production, which was increased in diabetic mice, was attenuated by CCX832. This was associated with an increase in Nox 4 expression. Augmented protein oxidation in db/db mice was not observed when mice were treated with CCX832. CCX832 also abrogated impaired Nrf2 nuclear activity and associated downregulation in antioxidants expression in kidneys from db/db mice. Our in vivo findings highlight the role of the redox signaling and Nrf2 system as renoprotective players during chemerin receptor blockade in diabetic mice. The chemerin/ChemR23 system may be an important target to limit renal dysfunction associated with obesity-related diabetes. Full article
(This article belongs to the Special Issue Roles of Cardiovascular Active Substances and Cellular Events in the Homeostasis of Cardiovascular Systems 2018)
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Review

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13 pages, 1056 KiB  
Review
Pulmonary Hypertension and Obesity: Focus on Adiponectin
by Fabio Perrotta, Ersilia Nigro, Mariano Mollica, Adriano Costigliola, Vito D’Agnano, Aurora Daniele, Andrea Bianco and Germano Guerra
Int. J. Mol. Sci. 2019, 20(4), 912; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20040912 - 20 Feb 2019
Cited by 42 | Viewed by 6437
Abstract
Pulmonary hypertension is an umbrella term including many different disorders causing an increase of the mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg. Recent data revealed a strong association between obesity and pulmonary hypertension. Adiponectin is a protein synthetized by the adipose tissue [...] Read more.
Pulmonary hypertension is an umbrella term including many different disorders causing an increase of the mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg. Recent data revealed a strong association between obesity and pulmonary hypertension. Adiponectin is a protein synthetized by the adipose tissue with pleiotropic effects on inflammation and cell proliferation, with a potential protective role on the pulmonary vasculature. Both in vivo and in vitro studies documented that adiponectin is an endogenous modulator of NO production and interferes with AMP-activated protein kinase (AMPK) activation, mammalian target of rapamycin (mTOR), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ) signaling preventing endothelial dysfunction and proliferation. Furthermore, adiponectin ameliorates insulin resistance by mediating the biological effects of peroxisome proliferator-activated receptor-gamma (PPARγ). Therefore, adiponectin modulation emerged as a theoretical target for the treatment of pulmonary hypertension, currently under investigation. Recently, consistent data showed that hypoglycemic agents targeting PPARγ as well as renin–angiotensin system inhibitors and mineralocorticoid receptor blockers may influence pulmonary hemodynamics in different models of pulmonary hypertension. Full article
(This article belongs to the Special Issue Roles of Cardiovascular Active Substances and Cellular Events in the Homeostasis of Cardiovascular Systems 2018)
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19 pages, 6850 KiB  
Review
The Role of Osteoprotegerin and Its Ligands in Vascular Function
by Luc Rochette, Alexandre Meloux, Eve Rigal, Marianne Zeller, Yves Cottin and Catherine Vergely
Int. J. Mol. Sci. 2019, 20(3), 705; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20030705 - 06 Feb 2019
Cited by 86 | Viewed by 9416
Abstract
The superfamily of tumor necrosis factor (TNF) receptors includes osteoprotegerin (OPG) and its ligands, which are receptor activators of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). The OPG/RANKL/RANK system plays an active role in pathological angiogenesis and inflammation as well [...] Read more.
The superfamily of tumor necrosis factor (TNF) receptors includes osteoprotegerin (OPG) and its ligands, which are receptor activators of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). The OPG/RANKL/RANK system plays an active role in pathological angiogenesis and inflammation as well as cell survival. It has been demonstrated that there is crosstalk between endothelial cells and osteoblasts during osteogenesis, thus establishing a connection between angiogenesis and osteogenesis. This OPG/RANKL/RANK/TRAIL system acts on specific cell surface receptors, which are then able to transmit their signals to other intracellular components and modify gene expression. Cytokine production and activation of their receptors induce mechanisms to recruit monocytes and neutrophils as well as endothelial cells. Data support the role of an increased OPG/RANKL ratio as a possible marker of progression of endothelial dysfunction in metabolic disorders in relationship with inflammatory marker levels. We review the role of the OPG/RANKL/RANK triad in vascular function as well as molecular mechanisms related to the etiology of vascular diseases. The potential therapeutic strategies may be very promising in the future. Full article
(This article belongs to the Special Issue Roles of Cardiovascular Active Substances and Cellular Events in the Homeostasis of Cardiovascular Systems 2018)
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13 pages, 633 KiB  
Review
Diuretic Effects of Sodium Glucose Cotransporter 2 Inhibitors and Their Influence on the Renin-Angiotensin System
by Tuba M. Ansary, Daisuke Nakano and Akira Nishiyama
Int. J. Mol. Sci. 2019, 20(3), 629; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20030629 - 01 Feb 2019
Cited by 115 | Viewed by 11684
Abstract
The renin-angiotensin system (RAS) plays an important role in regulating body fluids and blood pressure. However, inappropriate activation of the RAS contributes to the pathogenesis of cardiovascular and renal diseases. Recently, sodium glucose cotransporter 2 (SGLT2) inhibitors have been used as anti-diabetic agents. [...] Read more.
The renin-angiotensin system (RAS) plays an important role in regulating body fluids and blood pressure. However, inappropriate activation of the RAS contributes to the pathogenesis of cardiovascular and renal diseases. Recently, sodium glucose cotransporter 2 (SGLT2) inhibitors have been used as anti-diabetic agents. SGLT2 inhibitors induce glycosuria and improve hyperglycemia by inhibiting urinary reabsorption of glucose. However, in the early stages of treatment, these inhibitors frequently cause polyuria and natriuresis, which potentially activate the RAS. Nevertheless, the effects of SGLT2 inhibitors on RAS activity are not straightforward. Available data indicate that treatment with SGLT2 inhibitors transiently activates the systemic RAS in type 2 diabetic patients, but not the intrarenal RAS. In this review article, we summarize current evidence of the diuretic effects of SGLT2 inhibitors and their influence on RAS activity. Full article
(This article belongs to the Special Issue Roles of Cardiovascular Active Substances and Cellular Events in the Homeostasis of Cardiovascular Systems 2018)
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15 pages, 1399 KiB  
Review
IL-6: A Potential Role in Cardiac Metabolic Homeostasis
by Yitao Xu, Yubin Zhang and Junmei Ye
Int. J. Mol. Sci. 2018, 19(9), 2474; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19092474 - 21 Aug 2018
Cited by 30 | Viewed by 5238
Abstract
Interleukin-6 (IL-6) is implicated in multiple biological functions including immunity, neural development, and haematopoiesis. Recently, mounting evidence indicates that IL-6 plays a key role in metabolism, especially lipid metabolic homeostasis. A working heart requires a high and constant energy input which is largely [...] Read more.
Interleukin-6 (IL-6) is implicated in multiple biological functions including immunity, neural development, and haematopoiesis. Recently, mounting evidence indicates that IL-6 plays a key role in metabolism, especially lipid metabolic homeostasis. A working heart requires a high and constant energy input which is largely generated by fatty acid (FA) β-oxidation. Under pathological conditions, the precise balance between cardiac FA uptake and metabolism is perturbed so that excessive FA is accumulated, thereby predisposing to myocardial dysfunction (cardiac lipotoxicity). In this review, we summarize the current evidence that suggests the involvement of IL-6 in lipid metabolism. Cardiac metabolic features and consequences of myocardial lipotoxicity are also briefly analyzed. Finally, the roles of IL-6 in cardiac FA uptake (i.e., serum lipid profile and myocardial FA transporters) and FA metabolism (namely, β-oxidation, mitochondrial function, biogenesis, and FA de novo synthesis) are discussed. Overall, understanding how IL-6 transmits signals to affect lipid metabolism in the heart might allow for development of better clinical therapies for obesity-associated cardiac lipotoxicity. Full article
(This article belongs to the Special Issue Roles of Cardiovascular Active Substances and Cellular Events in the Homeostasis of Cardiovascular Systems 2018)
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