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Cellular and Molecular Biology of Cardiac Hypertrophy and Heart Failure: Pathogenesis, Diagnostics and Treatment

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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 (20 November 2024) | Viewed by 13310

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Prof. Dr. Morris Karmazyn

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Retired, Department of Physiology and Pharmacology, University of Western Ontario, London, ON N6G 2X6, Canada
Interests: cardiac hypertrophy; heart failure; sodium hydrogen exchange (NHE1); adipokines; traditional Chinese medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Heart failure is a major worldwide medical challenge in the 21st century. Although new therapeutic strategies have been developed, the incidence and mortality rates of heart failure are high, resulting in substantial personal, emotional and financial burdens. One roadblock to effectively treating heart failure is the complexity of cellular and molecular mechanisms underlying the remodelling process.

I am most pleased to announce that the International Journal of Molecular Sciences plans to devote a Special Issue on this subject entitled "Cellular and Molecular Biology of Cardiac Hypertrophy and Heart Failure: Pathogenesis, Diagnostics and Treatment". Manuscripts may be submitted in the form of either research papers or review articles and manuscripts related to either basic or clinical research.

Some of the general topics to be covered in the Special Issue include, but are not restricted to:

Cell signalling processes;
Energy metabolism;
Autophagy and mitophagy;
Apoptosis;
Ion (dys)regulation;
Mechanisms of increased dysrhythmogenesis;
Adipokines;
Hormonal and humoral factors;
Novel therapeutic approaches;
Natural plant-based therapeutics;
The gut microbiome.

Kind regards,

Prof. Dr. Morris Karmazyn
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

cardiac hypertrophy
myocardial remodelling
heart failure
cellular mechanisms
molecular mechanisms

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Published Papers (8 papers)

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Research

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12 pages, 944 KiB

Open AccessArticle

Low Plasma Carnosinase-1 Activity in Patients with Left Ventricular Systolic Dysfunction: Implications for Carnosine Therapy in Heart Failure

by I-Chau Liang, Ettore Gilardoni, Islam A. Berdaweel, Knute D. Carter and Ethan J. Anderson

Int. J. Mol. Sci. 2025, 26(6), 2608; https://doi.org/10.3390/ijms26062608 - 14 Mar 2025

Viewed by 556

Abstract

Therapeutic efficacy of histidyl dipeptides such as carnosine is hampered by circulating carnosinase-1 (CN1), which catalyzes carnosine’s hydrolysis and degradation. Prior reports suggest that oral carnosine may improve cardiometabolic parameters in patients with heart failure (HF), but whether CN1 activity is affected by HF is unknown. Here, we measured CN1 content and carnosine degradation rate (CDR) in preoperative plasma samples from a cohort of patients (n = 138) undergoing elective cardiac surgery to determine whether plasma CN1 and/or CDR varied with left ventricular (LV) systolic dysfunction. CN1 content was normally distributed in the cohort, but plasma CDR displayed a quasi-bimodal distribution into high- (>2 nmol/(h*μL)) and low-activity (≤2 nmol/(h*μL)) clusters. Multivariable analysis confirmed female sex, diabetes and LV systolic dysfunction was associated with the low-activity CDR cluster. Although CN1 content did not differ, logistic regression analysis revealed that CDR and CN1-specific activity (CDR/CN1 content) was significantly lower in patients with both moderate (ejection fraction, EF ≥ 35 to <50%) and severe LV systolic dysfunction (EF < 35%) compared with patients in the normal range (EF ≥ 50%). These findings suggest that plasma CN1 activity is regulated by factors independent of expression, and that a decline in LV systolic function is associated with low CN1 activity. Further studies are needed to delineate specific mechanisms controlling CN1 expression and activity, which will facilitate the development of carnosine and other histidyl dipeptide therapies for cardiometabolic disorders such as HF. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Cardiac Hypertrophy and Heart Failure: Pathogenesis, Diagnostics and Treatment)

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19 pages, 8503 KiB

Open AccessArticle

Molecular Mechanism of Aerobic Exercise Ameliorating Myocardial Mitochondrial Injury in Mice with Heart Failure

by Hao Jia, Yinping Song, Yijie Hua, Kunzhe Li, Sujuan Li and Youhua Wang

Int. J. Mol. Sci. 2025, 26(5), 2136; https://doi.org/10.3390/ijms26052136 - 27 Feb 2025

Viewed by 797

Abstract

To explore the molecular mechanism of aerobic exercise to improve heart failure and to provide a theoretical basis and experimental reference for the treatment of heart failure. Nine-week-old male mice were used to establish a left ventricular pressure overload-induced heart failure model by transverse aortic constriction (TAC). The mice were randomly divided into four groups: a sham group (SHAM), heart failure group (HF), heart failure + SKQ1 group (HS) and heart failure + aerobic exercise group (HE). The mice in the HE group were subjected to moderate-intensity aerobic exercise interventions. The mitochondrion-targeting antioxidant (SKQ1) contains the lipophilic cation TPP, which targets scavenging mitochondrial ROS. The HS group was subjected to SKQ1 (100 nmol/kg/d) interventions, which were initiated 1 week after the surgery, and the interventions lasted 8 weeks. Cardiac function was assessed by ultrasound, cardiomyocyte size by H&E and WGA staining, myocardial fibrosis by Masson’s staining, and myocardial tissue oxidative stress and apoptosis by DHE and TUNEL fluorescence staining, respectively. Western blotting was used to detect the expression of mitochondrial quality control, inflammation, and apoptosis-related proteins. In the cellular level, an in vitro cellular model was established by isolating primary cardiomyocytes from neonatal mice (2–3 days) and intervening with Ang II (1 μM) to mimic heart failure. Oxidative stress and mitochondrial membrane potential were determined in the cardiomyocytes of each group by DHE and JC-1 staining, respectively. Myocardial fibrosis was increased significantly and cardiac function was reduced significantly in the heart failure mice. Aerobic exercise and SKQ1 intervention improved cardiac function and reduced myocardial hypertrophy and myocardial fibrosis in the heart failure mice significantly. Meanwhile, aerobic exercise and SKQ1 intervention reduced the number of DHE-positive particles (p < 0.01) and inhibited myocardial oxidative stress in the heart failure mice significantly. Aerobic exercise also reduced DRP1, Parkin, and BNIP3 protein expression (p < 0.05, p < 0.01), and increased OPA1 and PINK1 protein expression (p < 0.05, p < 0.01) significantly. Moreover, aerobic exercise and SKQ1 intervention decreased the number of TUNEL-positive particles and the expression of inflammation- and apoptosis-related proteins NLRP3, TXNIP, Caspase-1, IL-1β, BAX, BAK, and p53 significantly (p < 0.05, p < 0.01). In addition, the AMPK agonist AICAR and the mitochondria-targeted ROS scavenger (SKQ1) ameliorated AngII-induced mitochondrial fragmentation and decreased mitochondrial membrane potential in cardiomyocytes significantly. It was shown that inhibition of mitochondrial ROS by aerobic exercise, which in turn inhibits mitochondrial damage, improves mitochondrial quality control, and reduces myocardial inflammatory and apoptosis, may be an important molecular mechanism by which aerobic exercise exerts endogenous antioxidant protective effects to improve cardiac function. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Cardiac Hypertrophy and Heart Failure: Pathogenesis, Diagnostics and Treatment)

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16 pages, 3616 KiB

Open AccessArticle

Altered Protein Kinase A-Dependent Phosphorylation of Cav1.2 in Left Ventricular Myocardium from Cacna1c Haploinsufficient Rat Hearts

by David Königstein, Hauke Fender, Jelena Plačkić, Theresa M. Kisko, Markus Wöhr and Jens Kockskämper

Int. J. Mol. Sci. 2024, 25(24), 13713; https://doi.org/10.3390/ijms252413713 - 22 Dec 2024

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Abstract

CACNA1C encodes the α1c subunit of the L-type Ca²⁺ channel, Cav1.2. Ventricular myocytes from haploinsufficient Cacna1c (Cacna1c^+/−) rats exhibited reduced expression of Cav1.2 but an apparently normal sarcolemmal Ca²⁺ influx with an impaired response to sympathetic stress. We tested the hypothesis that the altered phosphorylation of Cav1.2 might underlie the sarcolemmal Ca²⁺ influx phenotype in Cacna1c^+/− myocytes using immunoblotting of the left ventricular (LV) tissue from Cacna1c^+/− versus wildtype (WT) hearts. Activation of cAMP-dependent protein kinase A (PKA) increases L-type Ca²⁺ current and phosphorylates Cav1.2 at serine-1928. Using an antibody directed against this phosphorylation site, we observed elevated phosphorylation of Cav1.2 at serine-1928 in LV myocardium from Cacna1c^+/− rats under basal conditions (+110% versus WT). Sympathetic stress was simulated by isoprenaline (100 nM) in Langendorff-perfused hearts. Isoprenaline increased the phosphorylation of serine-1928 in Cacna1c^+/− LV myocardium by ≈410%, but the increase was significantly smaller than in WT myocardium (≈650%). In conclusion, our study reveals altered PKA-dependent phosphorylation of Cav1.2 with elevated phosphorylation of serine-1928 under basal conditions and a diminished phosphorylation reserve during β-adrenergic stimulation. These alterations in the phosphorylation of Cav1.2 may explain the apparently normal sarcolemmal Ca²⁺ influx in Cacna1c^+/− myocytes under basal conditions as well as the impaired response to sympathetic stimulation. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Cardiac Hypertrophy and Heart Failure: Pathogenesis, Diagnostics and Treatment)

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17 pages, 3106 KiB

Open AccessArticle

MicroRNA205: A Key Regulator of Cardiomyocyte Transition from Proliferative to Hypertrophic Growth in the Neonatal Heart

by Jonathan J. Weldrick, Rui Yi, Lynn A. Megeney and Patrick G. Burgon

Int. J. Mol. Sci. 2024, 25(4), 2206; https://doi.org/10.3390/ijms25042206 - 12 Feb 2024

Cited by 1 | Viewed by 1999

Abstract

The mammalian myocardium grows rapidly during early development due to cardiomyocyte proliferation, which later transitions to cell hypertrophy to sustain the heart’s postnatal growth. Although this cell transition in the postnatal heart is consistently preserved in mammalian biology, little is known about the regulatory mechanisms that link proliferation suppression with hypertrophy induction. We reasoned that the production of a micro-RNA(s) could serve as a key bridge to permit changes in gene expression that control the changed cell fate of postnatal cardiomyocytes. We used sequential expression analysis to identify miR205 as a micro-RNA that was uniquely expressed at the cessation of cardiomyocyte growth. Cardiomyocyte-specific miR205 deletion animals showed a 35% increase in heart mass by 3 months of age, with commensurate changes in cell cycle and Hippo pathway activity, confirming miR205’s potential role in controlling cardiomyocyte proliferation. In contrast, overexpression of miR205 in newborn hearts had little effect on heart size or function, indicating a complex, probably redundant regulatory system. These findings highlight miR205’s role in controlling the shift from cardiomyocyte proliferation to hypertrophic development in the postnatal period. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Cardiac Hypertrophy and Heart Failure: Pathogenesis, Diagnostics and Treatment)

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19 pages, 3280 KiB

Open AccessArticle

YB-1 Is a Novel Target for the Inhibition of α-Adrenergic-Induced Hypertrophy

by Jacqueline Heger, Stefan Partsch, Claudia Harjung, Zoltán V. Varga, Tamás Baranyai, Johannes Weiß, Lea Kremer, Fabian Locquet, Przemyslaw Leszek, Bence Ágg, Bettina Benczik, Péter Ferdinandy, Rainer Schulz and Gerhild Euler

Int. J. Mol. Sci. 2024, 25(1), 401; https://doi.org/10.3390/ijms25010401 - 28 Dec 2023

Cited by 2 | Viewed by 1968

Abstract

Cardiac hypertrophy resulting from sympathetic nervous system activation triggers the development of heart failure. The transcription factor Y-box binding protein 1 (YB-1) can interact with transcription factors involved in cardiac hypertrophy and may thereby interfere with the hypertrophy growth process. Therefore, the question arises as to whether YB-1 influences cardiomyocyte hypertrophy and might thereby influence the development of heart failure. YB-1 expression is downregulated in human heart biopsies of patients with ischemic cardiomyopathy (n = 8), leading to heart failure. To study the impact of reduced YB-1 in cardiac cells, we performed small interfering RNA (siRNA) experiments in H9C2 cells as well as in adult cardiomyocytes (CMs) of rats. The specificity of YB-1 siRNA was analyzed by a miRNA-like off-target prediction assay identifying potential genes. Testing three high-scoring genes by transfecting cardiac cells with YB-1 siRNA did not result in downregulation of these genes in contrast to YB-1, whose downregulation increased hypertrophic growth. Hypertrophic growth was mediated by PI3K under PE stimulation, as well by downregulation with YB-1 siRNA. On the other hand, overexpression of YB-1 in CMs, caused by infection with an adenovirus encoding YB-1 (AdYB-1), prevented hypertrophic growth under α-adrenergic stimulation with phenylephrine (PE), but not under stimulation with growth differentiation factor 15 (GDF15; n = 10–16). An adenovirus encoding the green fluorescent protein (AdGFP) served as the control. YB-1 overexpression enhanced the mRNA expression of the Gq inhibitor regulator of G-protein signaling 2 (RGS2) under PE stimulation (n = 6), potentially explaining its inhibitory effect on PE-induced hypertrophic growth. This study shows that YB-1 protects cardiomyocytes against PE-induced hypertrophic growth. Like in human end-stage heart failure, YB-1 downregulation may cause the heart to lose its protection against hypertrophic stimuli and progress to heart failure. Therefore, the transcription factor YB-1 is a pivotal signaling molecule, providing perspectives for therapeutic approaches. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Cardiac Hypertrophy and Heart Failure: Pathogenesis, Diagnostics and Treatment)

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16 pages, 1341 KiB

Open AccessReview

Behavior of Hypertrophied Right Ventricle during the Development of Left Ventricular Failure Due to Myocardial Infarction

by Naranjan S. Dhalla, Karina Oliveira Mota, Carla Maria Lins de Vasconcelos and Adriana Adameova

Int. J. Mol. Sci. 2024, 25(5), 2610; https://doi.org/10.3390/ijms25052610 - 23 Feb 2024

Cited by 2 | Viewed by 2177

Abstract

In order to determine the behavior of the right ventricle, we have reviewed the existing literature in the area of cardiac remodeling, signal transduction pathways, subcellular mechanisms, β-adrenoreceptor-adenylyl cyclase system and myocardial catecholamine content during the development of left ventricular failure due to myocardial infarction. The right ventricle exhibited adaptive cardiac hypertrophy due to increases in different signal transduction pathways involving the activation of protein kinase C, phospholipase C and protein kinase A systems by elevated levels of vasoactive hormones such as catecholamines and angiotensin II in the circulation at early and moderate stages of heart failure. An increase in the sarcoplasmic reticulum Ca²⁺ transport without any changes in myofibrillar Ca²⁺-stimulated ATPase was observed in the right ventricle at early and moderate stages of heart failure. On the other hand, the right ventricle showed maladaptive cardiac hypertrophy at the severe stages of heart failure due to myocardial infarction. The upregulation and downregulation of β-adrenoreceptor-mediated signal transduction pathways were observed in the right ventricle at moderate and late stages of heart failure, respectively. The catalytic activity of adenylate cyclase, as well as the regulation of this enzyme by G_s proteins, were seen to be augmented in the hypertrophied right ventricle at early, moderate and severe stages of heart failure. Furthermore, catecholamine stores and catecholamine uptake in the right ventricle were also affected as a consequence of changes in the sympathetic nervous system at different stages of heart failure. It is suggested that the hypertrophied right ventricle may serve as a compensatory mechanism to the left ventricle during the development of early and moderate stages of heart failure. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Cardiac Hypertrophy and Heart Failure: Pathogenesis, Diagnostics and Treatment)

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19 pages, 2467 KiB

Open AccessReview

Molecular and Cellular Mechanisms Underlying the Cardiac Hypertrophic and Pro-Remodelling Effects of Leptin

by Morris Karmazyn and Xiaohong Tracey Gan

Int. J. Mol. Sci. 2024, 25(2), 1137; https://doi.org/10.3390/ijms25021137 - 17 Jan 2024

Cited by 5 | Viewed by 1844

Abstract

Since its initial discovery in 1994, the adipokine leptin has received extensive interest as an important satiety factor and regulator of energy expenditure. Although produced primarily by white adipocytes, leptin can be synthesized by numerous tissues including those comprising the cardiovascular system. Cardiovascular function can thus be affected by locally produced leptin via an autocrine or paracrine manner but also by circulating leptin. Leptin exerts its effects by binding to and activating specific receptors, termed ObRs or LepRs, belonging to the Class I cytokine family of receptors of which six isoforms have been identified. Although all ObRs have identical intracellular domains, they differ substantially in length in terms of their extracellular domains, which determine their ability to activate cell signalling pathways. The most important of these receptors in terms of biological effects of leptin is the so-called long form (ObRb), which possesses the complete intracellular domain linked to full cell signalling processes. The heart has been shown to express ObRb as well as to produce leptin. Leptin exerts numerous cardiac effects including the development of hypertrophy likely through a number of cell signaling processes as well as mitochondrial dynamics, thus demonstrating substantial complex underlying mechanisms. Here, we discuss mechanisms that potentially mediate leptin-induced cardiac pathological hypertrophy, which may contribute to the development of heart failure. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Cardiac Hypertrophy and Heart Failure: Pathogenesis, Diagnostics and Treatment)

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21 pages, 5223 KiB

Open AccessCase Report

A Cautionary Tale of Hypertrophic Cardiomyopathy—From “Benign” Left Ventricular Hypertrophy to Stroke, Atrial Fibrillation, and Molecular Genetic Diagnostics: A Case Report and Review of Literature

by Dolina Gencheva, Petya Angelova, Kameliya Genova, Slavena Atemin, Mila Sleptsova, Tihomir Todorov, Fedya Nikolov, Donka Ruseva, Vanyo Mitev and Albena Todorova

Int. J. Mol. Sci. 2024, 25(17), 9385; https://doi.org/10.3390/ijms25179385 - 29 Aug 2024

Viewed by 1876

Abstract

This case report concerns a 48-year-old man with a history of ischemic stroke at the age of 41 who reported cardiac hypertrophy, registered in his twenties when explained by increased physical activity. Family history was positive for a mother with permanent atrial fibrillation from her mid-thirties. At the age of 44, he had a first episode of persistent atrial fibrillation, accompanied by left atrial thrombosis while on a direct oral anticoagulant. He presented at our clinic at the age of 45 with another episode of persistent atrial fibrillation and decompensated heart failure. Echocardiography revealed a dilated left atrium, reduced left ventricular ejection fraction, and an asymmetric left ventricular hypertrophy. Cardiac magnetic resonance was positive for a cardiomyopathy with diffuse fibrosis, while slow-flow phenomenon was present on coronary angiography. Genetic testing by whole-exome sequencing revealed three variants in the patient, c.309C > A, p.His103Gln in the ACTC1 gene, c.116T > G, p.Leu39Ter in the PLN gene, and c.5827C > T, p.His1943Tyr in the SCN5A gene, the first two associated with hypertrophic cardiomyopathy and the latter possibly with familial atrial fibrillation. This case illustrates the need for advanced diagnostics in unexplained left ventricular hypertrophy, as hypertrophic cardiomyopathy is often overlooked, leading to potentially debilitating health consequences. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Cardiac Hypertrophy and Heart Failure: Pathogenesis, Diagnostics and Treatment)

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