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Role of G-Protein Coupled Receptors in Cardiovascular Diseases
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Role of G-Protein Coupled Receptors in Cardiovascular Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 31569

Special Issue Editors

Dr. Emiel P.C. van der Vorst

E-Mail Website
Guest Editor
1. Interdisciplinary Center for Clinical Research (IZKF), 52056 Aachen, Germany
2. Institute for Molecular Cardiovascular Research (IMCAR), 52056 Aachen, Germany
3. Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), 52056 Aachen, Germany
4. Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU) München, 80337 Munich, Germany
Interests: cardiovascular disease; atherosclerosis; chemokines; lipids; inflammation
Special Issues, Collections and Topics in MDPI journals
Ms. Selin Gencer

E-Mail Website
Assistant Guest Editor
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU) München, Munich, Germany
Interests: atherosclerosis; cardiovascular disease; chemokine receptors; ACKR3

Special Issue Information

Dear Colleagues,

Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels, including coronary heart disease, cerebrovascular disease and thrombosis. Although over the years, significant efforts have been made to prevent or treat these diseases, it still remains one of the leading causes of death worldwide. The inflammatory processes in CVDs are facilitated by a network of circulating immune cells and tissue resident cells, which is orchestrated by various mediators which interact, bind and induce signaling. Over the last years, G protein coupled receptors (GPCRs) emerged as important players in recognizing these mediators, both in steady state and inflammatory processes like CVDs. GPCRs are seven-transmembrane domain receptors and can be subdivided in several sub-classes and subgroups. In order to better comprehend the pathology behind CVDs, it is important to obtain a good overview of the role of GPCRs and the underlying molecular mechanisms. Therefore, the present Special Issue aims to provide an current state-of-the-art overview of the role of GPCRs in CVDs.

Dr. Emiel P.C. van der Vorst
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • G-protein coupled receptors
  • atherosclerosis
  • vascular calcification
  • cardiomyopathy
  • heart failure
  • ischemic heart disease
  • thrombosis
  • cerebrovascular disease

Published Papers (6 papers)

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Editorial

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3 pages, 177 KiB  
Editorial
Role of G-Protein-Coupled Receptors in Cardiovascular Diseases
by Selin Gencer and Emiel P. C. van der Vorst
Int. J. Mol. Sci. 2023, 24(9), 7760; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24097760 - 24 Apr 2023
Viewed by 820
Abstract
Cardiovascular diseases (CVDs), such as ischemic heart disease and stroke, are recognized as major causes of deaths worldwide [...] Full article
(This article belongs to the Special Issue Role of G-Protein Coupled Receptors in Cardiovascular Diseases)

Research

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13 pages, 1747 KiB  
Article
Carvedilol Selectively Stimulates βArrestin2-Dependent SERCA2a Activity in Cardiomyocytes to Augment Contractility
by Jennifer Maning, Victoria L. Desimine, Celina M. Pollard, Jennifer Ghandour and Anastasios Lymperopoulos
Int. J. Mol. Sci. 2022, 23(19), 11315; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911315 - 26 Sep 2022
Cited by 8 | Viewed by 2006
Abstract
Heart failure (HF) carries the highest mortality in the western world and β-blockers [β-adrenergic receptor (AR) antagonists] are part of the cornerstone pharmacotherapy for post-myocardial infarction (MI) chronic HF. Cardiac β1AR-activated βarrestin2, a G protein-coupled receptor (GPCR) adapter protein, promotes Sarco(endo)plasmic [...] Read more.
Heart failure (HF) carries the highest mortality in the western world and β-blockers [β-adrenergic receptor (AR) antagonists] are part of the cornerstone pharmacotherapy for post-myocardial infarction (MI) chronic HF. Cardiac β1AR-activated βarrestin2, a G protein-coupled receptor (GPCR) adapter protein, promotes Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a SUMO (small ubiquitin-like modifier)-ylation and activity, thereby directly increasing cardiac contractility. Given that certain β-blockers, such as carvedilol and metoprolol, can activate βarrestins and/or SERCA2a in the heart, we investigated the effects of these two agents on cardiac βarrestin2-dependent SERCA2a SUMOylation and activity. We found that carvedilol, but not metoprolol, acutely induces βarrestin2 interaction with SERCA2a in H9c2 cardiomyocytes and in neonatal rat ventricular myocytes (NRVMs), resulting in enhanced SERCA2a SUMOylation. However, this translates into enhanced SERCA2a activity only in the presence of the β2AR-selective inverse agonist ICI 118,551 (ICI), indicating an opposing effect of carvedilol-occupied β2AR subtype on carvedilol-occupied β1AR-stimulated, βarrestin2-dependent SERCA2a activation. In addition, the amplitude of fractional shortening of NRVMs, transfected to overexpress βarrestin2, is acutely enhanced by carvedilol, again in the presence of ICI only. In contrast, metoprolol was without effect on NRVMs’ shortening amplitude irrespective of ICI co-treatment. Importantly, the pro-contractile effect of carvedilol was also observed in human induced pluripotent stem cell (hIPSC)-derived cardiac myocytes (CMs) overexpressing βarrestin2, and, in fact, it was present even without concomitant ICI treatment of human CMs. Metoprolol with or without concomitant ICI did not affect contractility of human CMs, either. In conclusion, carvedilol, but not metoprolol, stimulates βarrestin2-mediated SERCA2a SUMOylation and activity through the β1AR in cardiac myocytes, translating into direct positive inotropy. However, this unique βarrestin2-dependent pro-contractile effect of carvedilol may be opposed or masked by carvedilol-bound β2AR subtype signaling. Full article
(This article belongs to the Special Issue Role of G-Protein Coupled Receptors in Cardiovascular Diseases)
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16 pages, 4056 KiB  
Article
Orphan G-Protein Coupled Receptor GPRC5B Is Critical for Lymphatic Development
by Wenjing Xu, Nathan P. Nelson-Maney, László Bálint, Hyouk-Bum Kwon, Reema B. Davis, Danielle C. M. Dy, James M. Dunleavey, Brad St. Croix and Kathleen M. Caron
Int. J. Mol. Sci. 2022, 23(10), 5712; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105712 - 20 May 2022
Cited by 5 | Viewed by 2768
Abstract
Numerous studies have focused on the molecular signaling pathways that govern the development and growth of lymphatics in the hopes of elucidating promising druggable targets. G protein-coupled receptors (GPCRs) are currently the largest family of membrane receptors targeted by FDA-approved drugs, but there [...] Read more.
Numerous studies have focused on the molecular signaling pathways that govern the development and growth of lymphatics in the hopes of elucidating promising druggable targets. G protein-coupled receptors (GPCRs) are currently the largest family of membrane receptors targeted by FDA-approved drugs, but there remain many unexplored receptors, including orphan GPCRs with no known biological ligand or physiological function. Thus, we sought to illuminate the cadre of GPCRs expressed at high levels in lymphatic endothelial cells and identified four orphan receptors: GPRC5B, AGDRF5/GPR116, FZD8 and GPR61. Compared to blood endothelial cells, GPRC5B is the most abundant GPCR expressed in cultured human lymphatic endothelial cells (LECs), and in situ RNAscope shows high mRNA levels in lymphatics of mice. Using genetic engineering approaches in both zebrafish and mice, we characterized the function of GPRC5B in lymphatic development. Morphant gprc5b zebrafish exhibited failure of thoracic duct formation, and Gprc5b−/− mice suffered from embryonic hydrops fetalis and hemorrhage associated with subcutaneous edema and blood-filled lymphatic vessels. Compared to Gprc5+/+ littermate controls, Gprc5b−/− embryos exhibited attenuated developmental lymphangiogenesis. During the postnatal period, ~30% of Gprc5b−/− mice were growth-restricted or died prior to weaning, with associated attenuation of postnatal cardiac lymphatic growth. In cultured human primary LECs, expression of GPRC5B is required to maintain cell proliferation and viability. Collectively, we identify a novel role for the lymphatic-enriched orphan GPRC5B receptor in lymphangiogenesis of fish, mice and human cells. Elucidating the roles of orphan GPCRs in lymphatics provides new avenues for discovery of druggable targets to treat lymphatic-related conditions such as lymphedema and cancer. Full article
(This article belongs to the Special Issue Role of G-Protein Coupled Receptors in Cardiovascular Diseases)
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Review

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12 pages, 1411 KiB  
Review
The Role of GPR15 Function in Blood and Vasculature
by Mario Bauer
Int. J. Mol. Sci. 2021, 22(19), 10824; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910824 - 06 Oct 2021
Cited by 6 | Viewed by 2447
Abstract
Since the first prominent description of the orphan G protein-coupled receptor 15 (GPR15) on lymphocytes as a co-receptor for the human immunodeficiency virus (HIV) type 1 and 2 and the first report about the GPR15-triggered cytoprotective effect on vascular endothelial cells by recombinant [...] Read more.
Since the first prominent description of the orphan G protein-coupled receptor 15 (GPR15) on lymphocytes as a co-receptor for the human immunodeficiency virus (HIV) type 1 and 2 and the first report about the GPR15-triggered cytoprotective effect on vascular endothelial cells by recombinant human thrombomodulin, several decades passed before the GPR15 has been recently deorphanized. Because of new findings on GPR15, this review will summarize the consequences of GPR15 signaling considering the variety of GPR15-expressing cell types and of GPR15 ligands, with a focus on blood and vasculature. Full article
(This article belongs to the Special Issue Role of G-Protein Coupled Receptors in Cardiovascular Diseases)
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14 pages, 3209 KiB  
Review
Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and Cardiac Arrhythmias
by Henry Sutanto, Dobromir Dobrev and Jordi Heijman
Int. J. Mol. Sci. 2021, 22(16), 8994; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168994 - 20 Aug 2021
Cited by 22 | Viewed by 14724
Abstract
The renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiovascular health and disease. Short-term RAAS activation controls water and salt retention and causes vasoconstriction, which are beneficial for maintaining cardiac output in low blood pressure and early stage heart failure. However, prolonged RAAS [...] Read more.
The renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiovascular health and disease. Short-term RAAS activation controls water and salt retention and causes vasoconstriction, which are beneficial for maintaining cardiac output in low blood pressure and early stage heart failure. However, prolonged RAAS activation is detrimental, leading to structural remodeling and cardiac dysfunction. Natriuretic peptides (NPs) are activated to counterbalance the effect of RAAS and sympathetic nervous system by facilitating water and salt excretion and causing vasodilation. Neprilysin is a major NP-degrading enzyme that degrades multiple vaso-modulatory substances. Although the inhibition of neprilysin alone is not sufficient to counterbalance RAAS activation in cardiovascular diseases (e.g., hypertension and heart failure), a combination of angiotensin receptor blocker and neprilysin inhibitor (ARNI) was highly effective in several clinical trials and may modulate the risk of atrial and ventricular arrhythmias. This review summarizes the possible link between ARNI and cardiac arrhythmias and discusses potential underlying mechanisms, providing novel insights about the therapeutic role and safety profile of ARNI in the cardiovascular system. Full article
(This article belongs to the Special Issue Role of G-Protein Coupled Receptors in Cardiovascular Diseases)
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16 pages, 1474 KiB  
Review
Calcium-Sensing Receptor (CaSR), Its Impact on Inflammation and the Consequences on Cardiovascular Health
by Sai Sahana Sundararaman and Emiel P. C. van der Vorst
Int. J. Mol. Sci. 2021, 22(5), 2478; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052478 - 01 Mar 2021
Cited by 27 | Viewed by 7857
Abstract
The calcium Sensing Receptor (CaSR) is a cell surface receptor belonging to the family of G-protein coupled receptors. CaSR is mainly expressed by parathyroid glands, kidneys, bone, skin, adipose tissue, the gut, the nervous system, and the cardiovascular system. The receptor, as its [...] Read more.
The calcium Sensing Receptor (CaSR) is a cell surface receptor belonging to the family of G-protein coupled receptors. CaSR is mainly expressed by parathyroid glands, kidneys, bone, skin, adipose tissue, the gut, the nervous system, and the cardiovascular system. The receptor, as its name implies is involved in sensing calcium fluctuations in the extracellular matrix of cells, thereby having a major impact on the mineral homeostasis in humans. Besides calcium ions, the receptor is also activated by other di- and tri-valent cations, polypeptides, polyamines, antibiotics, calcilytics and calcimimetics, which upon binding induce intracellular signaling pathways. Recent studies have demonstrated that CaSR influences a wide variety of cells and processes that are involved in inflammation, the cardiovascular system, such as vascular calcification, atherosclerosis, myocardial infarction, hypertension, and obesity. Therefore, in this review, the current understanding of the role that CaSR plays in inflammation and its consequences on the cardiovascular system will be highlighted. Full article
(This article belongs to the Special Issue Role of G-Protein Coupled Receptors in Cardiovascular Diseases)
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