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Novel Strategies for Cardiac Protection and Regeneration

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 (25 August 2019) | Viewed by 29217

Special Issue Editor

Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy

Special Issue Information

Dear Colleagues,

The present Special Issue “Novel Strategies for Cardiac Protection and Regeneration” will cover a selection of the most recent scientific topics and current review articles in the field of basic and translational research dedicated to the improvement of the cardiac response to damage. Experimental papers, up-to-date review articles, and commentaries are all welcome.

Cardiovascular diseases are still one of the leading causes of death worldwide, as reported by the World Health Organization, and represent an enormous problem for modern society, and from an economic perspective, with a cost to the world healthcare system estimated to be about eight hundred and sixty billion dollars per year. Therefore, the development of novel, efficient, and cost-effective cardiac therapies is a fundamental worldwide goal.

Many efforts have been made in the past forty years to identify molecular mechanisms, which could be modulated in order reduce the negative consequences of cardiac injury. In particular, the most promising ones are based on the fine tuning of inflammatory and fibrotic cardiac responses, the regeneration of damaged cardiomyocytes, and the improvement of cardiac cells resistance to stress. Despite the fact that encouraging results have been obtained both in vitro and in vivo, a more in depth comprehension of the molecular aspects at the bases of cardiac protection and regeneration is mandatory before the clinical application of these strategies can be achieved.

Assoc. Prof. Luigi Anastasia
Guest Editor

Manuscript Submission Information

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Keywords

  • Heart dysfunction
  • Myocardial injury
  • Cardiac regeneration
  • Drug discovery
  • Stem cell therapies
  • Cardiac protection
  • Translational medicine
  • Cardiac fibrosis
  • Inflammation
  • Molecular mechanisms

Published Papers (6 papers)

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Research

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11 pages, 1730 KiB  
Article
Extracellular HtrA2 Induces Apoptosis in Human Umbilical Vein Endothelial Cells
by Gurpinder Kaur, Daniela Stallmann, Nancy Schanze, Rosmarie Laumann, Lukas Andreas Heger, Johannes Steinfurt, Peter Stachon, Karlheinz Peter, Christoph Bode, Martin Moser, Ingo Ahrens, Daniel Duerschmied and Marcus Hortmann
Int. J. Mol. Sci. 2019, 20(21), 5446; https://doi.org/10.3390/ijms20215446 - 31 Oct 2019
Cited by 4 | Viewed by 3529
Abstract
The serine protease high-temperature-required protein A2 (HtrA2) has been identified as a key intracellular molecule promoting apoptosis in cells during ischemia reperfusion (IR) injury. IR injury in ST-segment elevation myocardial infarction (STEMI) contributes to overall myocardial damage. HtrA2 has further been shown to [...] Read more.
The serine protease high-temperature-required protein A2 (HtrA2) has been identified as a key intracellular molecule promoting apoptosis in cells during ischemia reperfusion (IR) injury. IR injury in ST-segment elevation myocardial infarction (STEMI) contributes to overall myocardial damage. HtrA2 has further been shown to be significantly increased in the serum of patients with STEMI. In the present pilot study, we use human umbilical vein endothelial cells (HUVECs) to investigate whether extracellular HtrA2 induces apoptosis using Annexin V staining. Furthermore, we examine whether HtrA2 is released extracellularly after staurosporine-induced apoptosis using ELISA. We find that HtrA2 is released upon induction of apoptosis by staurosporine into the cell culture medium. Furthermore, treatment of HUVECs with extracellular HtrA2-induces apoptosis, while the addition of anti-HtrA2 antibodies reduces both HtrA2- and staurosporine-induced endothelial cell apoptosis. In conclusion, we show here that extracellular HtrA2 induces apoptosis in human endothelial cells, although the exact molecular mechanisms have to be investigated in future. Full article
(This article belongs to the Special Issue Novel Strategies for Cardiac Protection and Regeneration)
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18 pages, 2858 KiB  
Article
Pharmacological Targeting of KCa Channels to Improve Endothelial Function in the Spontaneously Hypertensive Rat
by Rayan Khaddaj Mallat, Cini Mathew John, Ramesh C Mishra, Dylan J Kendrick and Andrew P Braun
Int. J. Mol. Sci. 2019, 20(14), 3481; https://doi.org/10.3390/ijms20143481 - 16 Jul 2019
Cited by 1 | Viewed by 2330
Abstract
Systemic hypertension is a major risk factor for the development of cardiovascular disease and is often associated with endothelial dysfunction. KCa2.3 and KCa3.1 channels are expressed in the vascular endothelium and contribute to stimulus-evoked vasodilation. We hypothesized that acute treatment with SKA-31, a [...] Read more.
Systemic hypertension is a major risk factor for the development of cardiovascular disease and is often associated with endothelial dysfunction. KCa2.3 and KCa3.1 channels are expressed in the vascular endothelium and contribute to stimulus-evoked vasodilation. We hypothesized that acute treatment with SKA-31, a selective activator of KCa2.x and KCa3.1 channels, would improve endothelium-dependent vasodilation and transiently lower mean arterial pressure (MAP) in male, spontaneously hypertensive rats (SHRs). Isolated vascular preparations exhibited impaired vasodilation in response to bradykinin (i.e., endothelial dysfunction) compared with Wistar controls, which was associated with decreased bradykinin receptor expression in mesenteric arteries. In contrast, similar levels of endothelial KCa channel expression were observed, and SKA-31 evoked vasodilation was comparable in vascular preparations from both strains. Addition of a low concentration of SKA-31 (i.e., 0.2–0.3 μM) failed to augment bradykinin-induced vasodilation in arteries from SHRs. However, responses to acetylcholine were enhanced. Surprisingly, acute bolus administration of SKA-31 in vivo (30 mg/kg, i.p. injection) modestly elevated MAP compared with vehicle injection. In summary, pharmacological targeting of endothelial KCa channels in SHRs did not readily reverse endothelial dysfunction in situ, or lower MAP in vivo. SHRs thus appear to be less responsive to endothelial KCa channel activators, which may be related to their vascular pathology. Full article
(This article belongs to the Special Issue Novel Strategies for Cardiac Protection and Regeneration)
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Review

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36 pages, 745 KiB  
Review
Ischemia Reperfusion Injury: Mechanisms of Damage/Protection and Novel Strategies for Cardiac Recovery/Regeneration
by Andrea Caccioppo, Luca Franchin, Alberto Grosso, Filippo Angelini, Fabrizio D’Ascenzo and Maria Felice Brizzi
Int. J. Mol. Sci. 2019, 20(20), 5024; https://doi.org/10.3390/ijms20205024 - 11 Oct 2019
Cited by 55 | Viewed by 4858
Abstract
Ischemic diseases in an aging population pose a heavy social encumbrance. Moreover, current therapeutic approaches, which aimed to prevent or minimize ischemia-induced damage, are associated with relevant costs for healthcare systems. Early reperfusion by primary percutaneous coronary intervention (PPCI) has undoubtedly improved patient’s [...] Read more.
Ischemic diseases in an aging population pose a heavy social encumbrance. Moreover, current therapeutic approaches, which aimed to prevent or minimize ischemia-induced damage, are associated with relevant costs for healthcare systems. Early reperfusion by primary percutaneous coronary intervention (PPCI) has undoubtedly improved patient’s outcomes; however, the prevention of long-term complications is still an unmet need. To face these hurdles and improve patient’s outcomes, novel pharmacological and interventional approaches, alone or in combination, reducing myocardium oxygen consumption or supplying blood flow via collateral vessels have been proposed. A number of clinical trials are ongoing to validate their efficacy on patient’s outcomes. Alternative options, including stem cell-based therapies, have been evaluated to improve cardiac regeneration and prevent scar formation. However, due to the lack of long-term engraftment, more recently, great attention has been devoted to their paracrine mediators, including exosomes (Exo) and microvesicles (MV). Indeed, Exo and MV are both currently considered to be one of the most promising therapeutic strategies in regenerative medicine. As a matter of fact, MV and Exo that are released from stem cells of different origin have been evaluated for their healing properties in ischemia reperfusion (I/R) settings. Therefore, this review will first summarize mechanisms of cardiac damage and protection after I/R damage to track the paths through which more appropriate interventional and/or molecular-based targeted therapies should be addressed. Moreover, it will provide insights on novel non-invasive/invasive interventional strategies and on Exo-based therapies as a challenge for improving patient’s long-term complications. Finally, approaches for improving Exo healing properties, and topics still unsolved to move towards Exo clinical application will be discussed. Full article
(This article belongs to the Special Issue Novel Strategies for Cardiac Protection and Regeneration)
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22 pages, 275 KiB  
Review
Perioperative Cardioprotection by Remote Ischemic Conditioning
by Youn Joung Cho and Won Ho Kim
Int. J. Mol. Sci. 2019, 20(19), 4839; https://doi.org/10.3390/ijms20194839 - 29 Sep 2019
Cited by 26 | Viewed by 4776
Abstract
Remote ischemic conditioning has been investigated for cardioprotection to attenuate myocardial ischemia/reperfusion injury. In this review, we provide a comprehensive overview of the current knowledge of the signal transduction pathways of remote ischemic conditioning according to three stages: Remote stimulus from source organ; [...] Read more.
Remote ischemic conditioning has been investigated for cardioprotection to attenuate myocardial ischemia/reperfusion injury. In this review, we provide a comprehensive overview of the current knowledge of the signal transduction pathways of remote ischemic conditioning according to three stages: Remote stimulus from source organ; protective signal transfer through neuronal and humoral factors; and target organ response, including myocardial response and coronary vascular response. The neuronal and humoral factors interact on three levels, including stimulus, systemic, and target levels. Subsequently, we reviewed the clinical studies evaluating the cardioprotective effect of remote ischemic conditioning. While clinical studies of percutaneous coronary intervention showed relatively consistent protective effects, the majority of multicenter studies of cardiac surgery reported neutral results although there have been several promising initial trials. Failure to translate the protective effects of remote ischemic conditioning into cardiac surgery may be due to the multifactorial etiology of myocardial injury, potential confounding factors of patient age, comorbidities including diabetes, concomitant medications, and the coadministered cardioprotective general anesthetic agents. Given the complexity of signal transfer pathways and confounding factors, further studies should evaluate the multitarget strategies with optimal measures of composite outcomes. Full article
(This article belongs to the Special Issue Novel Strategies for Cardiac Protection and Regeneration)
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19 pages, 4859 KiB  
Review
Cardioprotective Melatonin: Translating from Proof-of-Concept Studies to Therapeutic Use
by Ovidiu Constantin Baltatu, Sergio Senar, Luciana Aparecida Campos and José Cipolla-Neto
Int. J. Mol. Sci. 2019, 20(18), 4342; https://doi.org/10.3390/ijms20184342 - 05 Sep 2019
Cited by 30 | Viewed by 7599
Abstract
In this review we summarized the actual clinical data for a cardioprotective therapeutic role of melatonin, listed melatonin and its agonists in different stages of development, and evaluated the melatonin cardiovascular target tractability and prediction using machine learning on ChEMBL. To date, most [...] Read more.
In this review we summarized the actual clinical data for a cardioprotective therapeutic role of melatonin, listed melatonin and its agonists in different stages of development, and evaluated the melatonin cardiovascular target tractability and prediction using machine learning on ChEMBL. To date, most clinical trials investigating a cardioprotective therapeutic role of melatonin are in phase 2a. Selective melatonin receptor agonists Tasimelteon, Ramelteon, and combined melatonergic-serotonin Agomelatine, and other agonists with registered structures in CHEMBL were not yet investigated as cardioprotective or cardiovascular drugs. As drug-able for these therapeutic targets, melatonin receptor agonists have the benefit over melatonin of well-characterized pharmacologic profiles and extensive safety data. Recent reports of the X-ray crystal structures of MT1 and MT2 receptors shall lead to the development of highly selective melatonin receptor agonists. Predictive models using machine learning could help to identify cardiovascular targets for melatonin. Selecting ChEMBL scores > 4.5 in cardiovascular assays, and melatonin scores > 4, we obtained 284 records from 162 cardiovascular assays carried out with 80 molecules with predicted or measured melatonin activity. Melatonin activities (agonistic or antagonistic) found in these experimental cardiovascular assays and models include arrhythmias, coronary and large vessel contractility, and hypertension. Preclinical proof-of-concept and early clinical studies (phase 2a) suggest a cardioprotective benefit from melatonin in various heart diseases. However, larger phase 3 randomized interventional studies are necessary to establish melatonin and its agonists’ actions as cardioprotective therapeutic agents. Full article
(This article belongs to the Special Issue Novel Strategies for Cardiac Protection and Regeneration)
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19 pages, 499 KiB  
Review
Left Ventricular Hypertrophy: Roles of Mitochondria CYP1B1 and Melatonergic Pathways in Co-Ordinating Wider Pathophysiology
by George Anderson and Gianluigi Mazzoccoli
Int. J. Mol. Sci. 2019, 20(16), 4068; https://doi.org/10.3390/ijms20164068 - 20 Aug 2019
Cited by 19 | Viewed by 5708
Abstract
Left ventricular hypertrophy (LVH) can be adaptive, as arising from exercise, or pathological, most commonly when driven by hypertension. The pathophysiology of LVH is consistently associated with an increase in cytochrome P450 (CYP)1B1 and mitogen-activated protein kinases (MAPKs) and a decrease in sirtuins [...] Read more.
Left ventricular hypertrophy (LVH) can be adaptive, as arising from exercise, or pathological, most commonly when driven by hypertension. The pathophysiology of LVH is consistently associated with an increase in cytochrome P450 (CYP)1B1 and mitogen-activated protein kinases (MAPKs) and a decrease in sirtuins and mitochondria functioning. Treatment is usually targeted to hypertension management, although it is widely accepted that treatment outcomes could be improved with cardiomyocyte hypertrophy targeted interventions. The current article reviews the wide, but disparate, bodies of data pertaining to LVH pathoetiology and pathophysiology, proposing a significant role for variations in the N-acetylserotonin (NAS)/melatonin ratio within mitochondria in driving the biological underpinnings of LVH. Heightened levels of mitochondria CYP1B1 drive the ‘backward’ conversion of melatonin to NAS, resulting in a loss of the co-operative interactions of melatonin and sirtuin-3 within mitochondria. NAS activates the brain-derived neurotrophic factor receptor, TrkB, leading to raised trophic signalling via cyclic adenosine 3′,5′-monophosphate (cAMP)-response element binding protein (CREB) and the MAPKs, which are significantly increased in LVH. The gut microbiome may be intimately linked to how stress and depression associate with LVH and hypertension, with gut microbiome derived butyrate, and other histone deacetylase inhibitors, significant modulators of the melatonergic pathways and LVH more generally. This provides a model of LVH that has significant treatment and research implications. Full article
(This article belongs to the Special Issue Novel Strategies for Cardiac Protection and Regeneration)
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