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Pharmacological Conditioning of the Heart-Molecular Targets

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

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 10523

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Special Issue Editors

Prof. Dr. Markus W. Hollmann

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Guest Editor

Department of Anesthesiology, Amsterdam University Medical Center (AUMC), Amsterdam, The Netherlands
Interests: pain management; fluid management; neuromuscular management; chronic pain, regional anesthesia; pharmacology; cardioprotection; intraoperative ventilation; local anesthetics
Special Issues, Collections and Topics in MDPI journals

Dr. Nina Hauck-Weber

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Guest Editor

Department of Anesthesiology, Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

Special Issue Information

Dear Colleagues,

Decades after the first investigations of Murry and colleagues discovering the phenomenon of conditioning the heart, we still seek a way to translate this powerful tool into clinical settings and to the patient who suffers from ischemic heart diseases. Thousands of publications have revealed several molecular mechanisms that translate the initial stimulus to the protection of the heart, yet none of the approaches has successfully been used in a large patient population. This is mostly explained by the fact that all animal and in vitro experiments are not able to reflect the clinical situation close enough, and several studies are performed in healthy animals or cells, lacking underlying co-morbidities, the relevant anesthetic regime and other important factors. However, revealing different molecular mechanisms and targets involved in cardioprotection is exactly the right way to translate the phenomenon of conditioning the heart to the clinic. By identifying different druggable interventions, we can learn to understand how we can prime the heart against a lethal ischemic stimulus.
Therefore, with this themed issue, we welcome all research that focuses on conditioning of the heart, with a special focus on revealing the molecular targets involved in conditioning.

Dr. Markus W. Hollmann
Dr. Nina Hauck-Weber
Guest Editors

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.

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Keywords

Conditioning
pre and post conditioning
heart, survival kinases
RISK pathway
SAVE pathway
ischemia-reperfusion injury
protein kinases
comorbidities
mitochondria
mechanisms
caveolins

Published Papers (4 papers)

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Research

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13 pages, 1862 KiB

Open AccessArticle

Combination of Cyclosporine A and Levosimendan Induces Cardioprotection under Acute Hyperglycemia

by Carolin Torregroza, Birce Yueksel, Raphael Ruske, Martin Stroethoff, Annika Raupach, André Heinen, Markus W. Hollmann, Ragnar Huhn and Katharina Feige

Int. J. Mol. Sci. 2021, 22(9), 4517; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094517 - 26 Apr 2021

Cited by 7 | Viewed by 2000

Abstract

Prognosis of patients with myocardial infarction is detrimentally affected by comorbidities like diabetes mellitus. In the experimental setting, not only diabetes mellitus but also acute hyperglycemia is shown to hamper cardioprotective properties by multiple pharmacological agents. For Levosimendan-induced postconditioning, a strong infarct size reducing effect is demonstrated in healthy myocardium. However, acute hyperglycemia is suggested to block this protective effect. In the present study, we investigated whether (1) Levosimendan-induced postconditioning exerts a concentration-dependent effect under hyperglycemic conditions and (2) whether a combination with the mitochondrial permeability transition pore (mPTP) blocker cyclosporine A (CsA) restores the cardioprotective properties of Levosimendan under hyperglycemia. For this experimental investigation, hearts of male Wistar rats were randomized and mounted onto a Langendorff system, perfused with Krebs-Henseleit buffer with a constant pressure of 80 mmHg. All isolated hearts were subjected to 33 min of global ischemia and 60 min of reperfusion under hyperglycemic conditions. (1) Hearts were perfused with various concentrations of Levosimendan (Lev) (0.3–10 μM) for 10 min at the onset of reperfusion, in order to investigate a concentration–response relationship. In the second set of experiments (2), 0.3 μM Levosimendan was administered in combination with the mPTP blocker CsA, to elucidate the underlying mechanism of blocked cardioprotection under hyperglycemia. Infarct size was determined by tetrazolium chloride (TTC) staining. (1) Control (Con) hearts showed an infarct size of 52 ± 12%. None of the administered Levosimendan concentrations reduced the infarct size (Lev0.3: 49 ± 9%; Lev1: 57 ± 9%; Lev3: 47 ± 11%; Lev10: 50 ± 7%; all ns vs. Con). (2) Infarct size of Con and Lev0.3 hearts were 53 ± 4% and 56 ± 2%, respectively. CsA alone had no effect on infarct size (CsA: 50 ± 10%; ns vs. Con). The combination of Lev0.3 and CsA (Lev0.3 ± CsA) induced a significant infarct size reduction compared to Lev0.3 (Lev0.3+CsA: 35 ± 4%; p < 0.05 vs. Lev0.3). We demonstrated that (1) hyperglycemia blocks the infarct size reducing effects of Levosimendan-induced postconditioning and cannot be overcome by an increased concentration. (2) Furthermore, cardioprotection under hyperglycemia can be restored by combining Levosimendan and the mPTP blocker CsA. Full article

(This article belongs to the Special Issue Pharmacological Conditioning of the Heart-Molecular Targets)

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10 pages, 957 KiB

Open AccessArticle

Cardioprotective Properties of Mannitol—Involvement of Mitochondrial Potassium Channels

by Katharina Feige, Janine Rubbert, Annika Raupach, Martin Stroethoff, André Heinen, Markus W. Hollmann, Ragnar Huhn and Carolin Torregroza

Int. J. Mol. Sci. 2021, 22(5), 2395; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052395 - 27 Feb 2021

Cited by 10 | Viewed by 2399

Abstract

Cardiac preconditioning (PC) and postconditioning (PoC) are powerful measures against the consequences of myocardial ischemia and reperfusion (I/R) injury. Mannitol—a hyperosmolar solution—is clinically used for treatment of intracranial and intraocular pressure or promotion of diuresis in renal failure. Next to these clinical indications, different organ-protective properties—e.g., perioperative neuroprotection—are described. However, whether Mannitol also confers cardioprotection via a pre- and/or postconditioning stimulus, possibly reducing consequences of I/R injury, remains to be seen. Therefore, in the present study we investigated whether (1) Mannitol-induced pre- and/or postconditioning induces myocardial infarct size reduction and (2) activation of mitochondrial ATP-sensitive potassium (mK_ATP) channels is involved in cardioprotection by Mannitol. Experiments were performed on isolated hearts of male Wistar rats via a pressure controlled Langendorff system, randomized into 7 groups. Each heart underwent 33 min of global ischemia and 60 min of reperfusion. Control hearts (Con) received Krebs–Henseleit buffer as vehicle only. Pre- and postconditioning was achieved by administration of 11 mmol/L Mannitol for 10 min before ischemia (Man-PC) or immediately at the onset of reperfusion (Man-PoC), respectively. In further groups, the mK_ATP channel blocker 5HD, was applied with and without Mannitol, to determine the potential underlying cardioprotective mechanisms. Primary endpoint was infarct size, determined by triphenyltetrazolium chloride staining. Mannitol significantly reduced infarct size both as a pre- (Man-PC) and postconditioning (Man-PoC) stimulus compared to control hearts (Man-PC: 31 ± 4%; Man-PoC: 35 ± 6%, each p < 0.05 vs. Con: 57 ± 9%). The mK_ATP channel inhibitor completely abrogated the cardioprotective effect of Mannitol-induced pre- (5HD-PC-Man-PC: 59 ± 8%, p < 0.05 vs. Man-PC) and postconditioning (5HD-PoC-Man-PoC: 59 ± 10% vs. p < 0.05 Man-PoC). Infarct size was not influenced by 5HD itself (5HD-PC: 60 ± 14%; 5HD-PoC: 54 ± 14%, each ns vs. Con). This study demonstrates that Mannitol (1) induces myocardial pre- and postconditioning and (2) confers cardioprotection via activation of mK_ATP channels. Full article

(This article belongs to the Special Issue Pharmacological Conditioning of the Heart-Molecular Targets)

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Review

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21 pages, 2530 KiB

Open AccessReview

Mitochondria and Pharmacologic Cardiac Conditioning—At the Heart of Ischemic Injury

by Christopher Lotz, Johannes Herrmann, Quirin Notz, Patrick Meybohm and Franz Kehl

Int. J. Mol. Sci. 2021, 22(6), 3224; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063224 - 22 Mar 2021

Cited by 11 | Viewed by 3464

Abstract

Pharmacologic cardiac conditioning increases the intrinsic resistance against ischemia and reperfusion (I/R) injury. The cardiac conditioning response is mediated via complex signaling networks. These networks have been an intriguing research field for decades, largely advancing our knowledge on cardiac signaling beyond the conditioning response. The centerpieces of this system are the mitochondria, a dynamic organelle, almost acting as a cell within the cell. Mitochondria comprise a plethora of functions at the crossroads of cell death or survival. These include the maintenance of aerobic ATP production and redox signaling, closely entwined with mitochondrial calcium handling and mitochondrial permeability transition. Moreover, mitochondria host pathways of programmed cell death impact the inflammatory response and contain their own mechanisms of fusion and fission (division). These act as quality control mechanisms in cellular ageing, release of pro-apoptotic factors and mitophagy. Furthermore, recently identified mechanisms of mitochondrial regeneration can increase the capacity for oxidative phosphorylation, decrease oxidative stress and might help to beneficially impact myocardial remodeling, as well as invigorate the heart against subsequent ischemic insults. The current review highlights different pathways and unresolved questions surrounding mitochondria in myocardial I/R injury and pharmacological cardiac conditioning. Full article

(This article belongs to the Special Issue Pharmacological Conditioning of the Heart-Molecular Targets)

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19 pages, 713 KiB

Open AccessReview

Pharmacological Conditioning of the Heart: An Update on Experimental Developments and Clinical Implications

by Sebastian Roth, Carolin Torregroza, Katharina Feige, Benedikt Preckel, Markus W. Hollmann, Nina C. Weber and Ragnar Huhn

Int. J. Mol. Sci. 2021, 22(5), 2519; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052519 - 03 Mar 2021

Cited by 15 | Viewed by 2049

Abstract

The aim of pharmacological conditioning is to protect the heart against myocardial ischemia-reperfusion (I/R) injury and its consequences. There is extensive literature that reports a multitude of different cardioprotective signaling molecules and mechanisms in diverse experimental protocols. Several pharmacological agents have been evaluated in terms of myocardial I/R injury. While results from experimental studies are immensely encouraging, translation into the clinical setting remains unsatisfactory. This narrative review wants to focus on two aspects: (1) give a comprehensive update on new developments of pharmacological conditioning in the experimental setting concentrating on recent literature of the last two years and (2) briefly summarize clinical evidence of these cardioprotective substances in the perioperative setting highlighting their clinical implications. By directly opposing each pharmacological agent regarding its recent experimental knowledge and most important available clinical data, a clear overview is given demonstrating the remaining gap between basic research and clinical practice. Finally, future perspectives are given on how we might overcome the limited translatability in the field of pharmacological conditioning. Full article

(This article belongs to the Special Issue Pharmacological Conditioning of the Heart-Molecular Targets)

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