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Diabetes & Metabolism Journal Jan 2024Insulin resistance has been regarded as a hallmark of diabetes heart disease (DHD). Numerous studies have shown that insulin resistance can affect blood circulation and... (Review)
Review
Insulin resistance has been regarded as a hallmark of diabetes heart disease (DHD). Numerous studies have shown that insulin resistance can affect blood circulation and myocardium, which indirectly cause cardiac hypertrophy and ventricular remodeling, participating in the pathogenesis of DHD. Meanwhile, hyperinsulinemia, hyperglycemia, and hyperlipidemia associated with insulin resistance can directly impair the metabolism and function of the heart. Targeting insulin resistance is a potential therapeutic strategy for the prevention of DHD. Currently, the role of insulin resistance in the pathogenic development of DHD is still under active research, as the pathological roles involved are complex and not yet fully understood, and the related therapeutic approaches are not well developed. In this review, we describe insulin resistance and add recent advances in the major pathological and physiological changes and underlying mechanisms by which insulin resistance leads to myocardial remodeling and dysfunction in the diabetic heart, including exosomal dysfunction, ferroptosis, and epigenetic factors. In addition, we discuss potential therapeutic approaches to improve insulin resistance and accelerate the development of cardiovascular protection drugs.
Topics: Humans; Insulin Resistance; Diabetes Mellitus; Myocardium; Heart; Heart Diseases
PubMed: 38173376
DOI: 10.4093/dmj.2023.0110 -
Physiological Reports Sep 2023The cardiovascular system is primarily controlled by the autonomic nervous system, and any changes in sympathetic or parasympathetic activity also have an impact on... (Review)
Review
The cardiovascular system is primarily controlled by the autonomic nervous system, and any changes in sympathetic or parasympathetic activity also have an impact on myocardial activity. Heart rate variability (HRV) is a readily available metric used to assess heart rate control by the autonomic nervous system. HRV can provide information about neural (parasympathetic, sympathetic, reflex) and humoral (hormones, thermoregulation) control of myocardial activity. Because there are no relevant reference values for HRV parameters in rats in the scientific literature, all experimental results are only interpreted on the basis of changes from currently measured control or baseline HRV values, which are, however, significantly different in individual studies. Considering the significant variability of published HRV data, the present study focused primarily on comparing control or baseline HRV values under different conditions in in vivo experiments involving rats. The aim of the study was therefore to assess whether there are differences in the starting values before the experiment itself.
Topics: Male; Animals; Rats; Heart Rate; Autonomic Nervous System; Body Temperature Regulation; Myocardium; Reference Values
PubMed: 37735345
DOI: 10.14814/phy2.15827 -
Biochemical Pharmacology Jan 2024An important mechanism for cancer progression is degradation of the extracellular matrix (ECM) which is accompanied by the emergence and proliferation of an activated... (Review)
Review
An important mechanism for cancer progression is degradation of the extracellular matrix (ECM) which is accompanied by the emergence and proliferation of an activated fibroblast, termed the cancer associated fibroblast (CAF). More specifically, an enzyme pathway identified to be amplified with local cancer progression and proliferation of the CAF, is fibroblast activation protein (FAP). The development and progression of heart failure (HF) irrespective of the etiology is associated with left ventricular (LV) remodeling and changes in ECM structure and function. As with cancer, HF progression is associated with a change in LV myocardial fibroblast growth and function, and expresses a protein signature not dissimilar to the CAF. The overall goal of this review is to put forward the postulate that scientific discoveries regarding FAP in cancer as well as the development of specific chemotherapeutics could be pivoted to target the emergence of FAP in the activated fibroblast subtype and thus hold translationally relevant diagnostic and therapeutic targets in HF.
Topics: Humans; Heart Failure; Myocardium; Fibroblasts; Extracellular Matrix; Neoplasms; Ventricular Remodeling
PubMed: 37956895
DOI: 10.1016/j.bcp.2023.115914 -
Circulation Research Jun 2024Fibroblasts are essential for building and maintaining the structural integrity of all organs. Moreover, fibroblasts can acquire an inflammatory phenotype to accommodate... (Review)
Review
Fibroblasts are essential for building and maintaining the structural integrity of all organs. Moreover, fibroblasts can acquire an inflammatory phenotype to accommodate immune cells in specific niches and to provide migration, differentiation, and growth factors. In the heart, balancing of fibroblast activity is critical for cardiac homeostasis and optimal organ function during inflammation. Fibroblasts sustain cardiac homeostasis by generating local niche environments that support housekeeping functions and by actively engaging in intercellular cross talk. During inflammatory perturbations, cardiac fibroblasts rapidly switch to an inflammatory state and actively communicate with infiltrating immune cells to orchestrate immune cell migration and activity. Here, we summarize the current knowledge on the molecular landscape of cardiac fibroblasts, focusing on their dual role in promoting tissue homeostasis and modulating immune cell-cardiomyocyte interaction. In addition, we discuss potential future avenues for manipulating cardiac fibroblast activity during myocardial inflammation.
Topics: Humans; Homeostasis; Animals; Fibroblasts; Myocardium; Inflammation; Myocarditis; Myocytes, Cardiac; Cell Communication
PubMed: 38843287
DOI: 10.1161/CIRCRESAHA.124.323892 -
Nature Communications Jul 2023Epigenetic regulation of histone H3K27 methylation has recently emerged as a key step during alternative immunoregulatory M2-like macrophage polarization; known to...
Epigenetic regulation of histone H3K27 methylation has recently emerged as a key step during alternative immunoregulatory M2-like macrophage polarization; known to impact cardiac repair after Myocardial Infarction (MI). We hypothesized that EZH2, responsible for H3K27 methylation, could act as an epigenetic checkpoint regulator during this process. We demonstrate for the first time an ectopic EZH2, and putative, cytoplasmic inactive localization of the epigenetic enzyme, during monocyte differentiation into M2 macrophages in vitro as well as in immunomodulatory cardiac macrophages in vivo in the post-MI acute inflammatory phase. Moreover, we show that pharmacological EZH2 inhibition, with GSK-343, resolves H3K27 methylation of bivalent gene promoters, thus enhancing their expression to promote human monocyte repair functions. In line with this protective effect, GSK-343 treatment accelerated cardiac inflammatory resolution preventing infarct expansion and subsequent cardiac dysfunction in female mice post-MI in vivo. In conclusion, our study reveals that pharmacological epigenetic modulation of cardiac-infiltrating immune cells may hold promise to limit adverse cardiac remodeling after MI.
Topics: Animals; Female; Humans; Mice; Cell Differentiation; Epigenesis, Genetic; Macrophages; Mice, Inbred C57BL; Monocytes; Myocardial Infarction; Myocardium
PubMed: 37491334
DOI: 10.1038/s41467-023-40186-0 -
Annual Review of Physiology Feb 2024Force generation in striated muscle is primarily controlled by structural changes in the actin-containing thin filaments triggered by an increase in intracellular... (Review)
Review
Force generation in striated muscle is primarily controlled by structural changes in the actin-containing thin filaments triggered by an increase in intracellular calcium concentration. However, recent studies have elucidated a new class of regulatory mechanisms, based on the myosin-containing thick filament, that control the strength and speed of contraction by modulating the availability of myosin motors for the interaction with actin. This review summarizes the mechanisms of thin and thick filament activation that regulate the contractility of skeletal and cardiac muscle. A novel dual-filament paradigm of muscle regulation is emerging, in which the dynamics of force generation depends on the coordinated activation of thin and thick filaments. We highlight the interfilament signaling pathways based on titin and myosin-binding protein-C that couple thin and thick filament regulatory mechanisms. This dual-filament regulation mediates the length-dependent activation of cardiac muscle that underlies the control of the cardiac output in each heartbeat.
Topics: Humans; Actins; Muscle, Skeletal; Myocardium; Myosins; Actin Cytoskeleton; Calcium
PubMed: 37931167
DOI: 10.1146/annurev-physiol-042222-022728 -
Development (Cambridge, England) Nov 2023Reciprocal interactions between non-myocytes and cardiomyocytes regulate cardiac growth and differentiation. Here, we report that the transcription factor Ebf1 is highly...
Reciprocal interactions between non-myocytes and cardiomyocytes regulate cardiac growth and differentiation. Here, we report that the transcription factor Ebf1 is highly expressed in non-myocytes and potently regulates heart development. Ebf1-deficient hearts display myocardial hypercellularity and reduced cardiomyocyte size, ventricular conduction system hypoplasia, and conduction system disease. Growth abnormalities in Ebf1 knockout hearts are observed as early as embryonic day 13.5. Transcriptional profiling of Ebf1-deficient embryonic cardiac non-myocytes demonstrates dysregulation of Polycomb repressive complex 2 targets, and ATAC-Seq reveals altered chromatin accessibility near many of these same genes. Gene set enrichment analysis of differentially expressed genes in cardiomyocytes isolated from E13.5 hearts of wild-type and mutant mice reveals significant enrichment of MYC targets and, consistent with this finding, we observe increased abundance of MYC in mutant hearts. EBF1-deficient non-myocytes, but not wild-type non-myocytes, are sufficient to induce excessive accumulation of MYC in co-cultured wild-type cardiomyocytes. Finally, we demonstrate that BMP signaling induces Ebf1 expression in embryonic heart cultures and controls a gene program enriched in EBF1 targets. These data reveal a previously unreported non-cell-autonomous pathway controlling cardiac growth and differentiation.
Topics: Animals; Mice; Cell Differentiation; Gene Expression Regulation; Myocardium; Myocytes, Cardiac; Transcription Factors
PubMed: 37787076
DOI: 10.1242/dev.202054 -
Science Advances Dec 2023Mammals have limited capacity for heart regeneration, whereas zebrafish have extraordinary regeneration abilities. During zebrafish heart regeneration, endothelial cells...
Mammals have limited capacity for heart regeneration, whereas zebrafish have extraordinary regeneration abilities. During zebrafish heart regeneration, endothelial cells promote cardiomyocyte cell cycle reentry and myocardial repair, but the mechanisms responsible for promoting an injury microenvironment conducive to regeneration remain incompletely defined. Here, we identify the matrix metalloproteinase Mmp14b as an essential regulator of heart regeneration. We identify a TEAD-dependent endothelial enhancer induced by heart injury in zebrafish and mice, and we show that the enhancer is required for regeneration, supporting a role for Hippo signaling upstream of . Last, we show that MMP-14 function in mice is important for the accumulation of Agrin, an essential regulator of neonatal mouse heart regeneration. These findings reveal mechanisms for extracellular matrix remodeling that promote heart regeneration.
Topics: Animals; Mice; Zebrafish; Endothelial Cells; Myocardium; Myocytes, Cardiac; Cell Proliferation; Regeneration; Mammals
PubMed: 38019918
DOI: 10.1126/sciadv.adh5313 -
European Heart Journal. Cardiovascular... Dec 2023The pathophysiological hallmark of cardiac amyloidosis (CA) is the deposition of amyloid within the myocardium. Consequently, extracellular volume (ECV) of affected... (Observational Study)
Observational Study
AIMS
The pathophysiological hallmark of cardiac amyloidosis (CA) is the deposition of amyloid within the myocardium. Consequently, extracellular volume (ECV) of affected patients increases. However, studies on ECV progression over time are lacking. We aimed to investigate the progression of ECV and its prognostic impact in CA patients.
METHODS AND RESULTS
Serial cardiac magnetic resonance (CMR) examinations, including ECV quantification, were performed in consecutive CA patients. Between 2012 and 2021, 103 CA patients underwent baseline and follow-up CMR, including ECV quantification. Median ECVs at baseline of the total (n = 103), transthyretin [(ATTR) n = 80], and [light chain (AL) n = 23] CA cohorts were 48.0%, 49.0%, and 42.6%, respectively. During a median period of 12 months, ECV increased significantly in all cohorts [change (Δ) +3.5% interquartile range (IQR): -1.9 to +6.9, P < 0.001; Δ +3.5%, IQR: -2.0 to +6.7, P < 0.001; and Δ +3.5%, IQR: -1.6 to +9.1, P = 0.026]. Separate analyses for treatment-naïve (n = 21) and treated (n = 59) ATTR patients revealed that the median change of ECV from baseline to follow-up was significantly higher among untreated patients (+5.7% vs. +2.3%, P = 0.004). Survival analyses demonstrated that median change of ECV was a predictor of outcome [total: hazard ratio (HR): 1.095, 95% confidence interval (CI): 1.047-1.0145, P < 0.001; ATTR: HR: 1.073, 95% CI: 1.015-1.134, P = 0.013; and AL: HR: 1.131, 95% CI: 1.041-1.228, P = 0.003].
CONCLUSION
The present study supports the use of serial ECV quantification in CA patients, as change of ECV was a predictor of outcome and could provide information in the evaluation of amyloid-specific treatments.
Topics: Humans; Amyloidosis; Cardiomyopathies; Contrast Media; Magnetic Resonance Imaging, Cine; Myocardium; Predictive Value of Tests; Registries; Prospective Studies
PubMed: 37549339
DOI: 10.1093/ehjci/jead188 -
Canadian Journal of Physiology and... Dec 2023The purpose of this study was to characterize the role of β-AR signaling and its cross-talk between cardiac renin-angiotensin system and thyroid-hormone-induced cardiac... (Review)
Review
The purpose of this study was to characterize the role of β-AR signaling and its cross-talk between cardiac renin-angiotensin system and thyroid-hormone-induced cardiac hypertrophy. T was administered at 0.5 mg·kg·day for 10 days in β1-KO and WT groups, while control groups received vehicle alone. Echocardiography and myocardial histology was performed; cardiac and serum ANGI/ANGII and ANP and cardiac levels of p-PKA, p-ERK1/2, p-p38-MAPK, p-AKT, p-4EBP1, and ACE were measured. WT showed decreased IVST and increased LVEDD versus WT ( < 0.05). β1-KO exhibited lower LVEDD and higher relative IVST versus β1-KO, the lowest levels of ejection fraction, and the highest levels of cardiomyocyte diameter ( < 0.05). Cardiac ANP levels decreased in WT versus β1-KO ( < 0.05). Cardiac ACE expression was increased in T-treated groups ( < 0.05). Phosphorylated-p38 MAPK levels were higher in WT versus WT or β1-KO p-4EBP1 was elevated in β1-KO animals, and p-ERK1/2 was up-regulated in β1-KO. These findings suggest that β-AR signaling is crucial for TiCH.
Topics: Mice; Animals; Cardiomyopathy, Restrictive; Mice, Knockout; Myocardium; Thyroid Hormones; Receptors, Adrenergic; Angiotensin II
PubMed: 37747059
DOI: 10.1139/cjpp-2023-0153