Chymase uptake by cardiomyocytes results in myosin degradation in cardiac volume overload

Powell, Pamela C.; Wei, Chih‐Chang; Fu, Lianwu; Pat, Betty; Bradley, Wayne E.; Collawn, James F.; Dell’Italia, Louis J.

doi:10.1016/j.heliyon.2019.e01397

Cited by 13 publications

(9 citation statements)

References 36 publications

(71 reference statements)

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“…Corresponding to the heightened gene expression levels of MCP-1 and MCP-5, but not the other MCPs, in hearts of hypertensive and normotensive female rats (19), we show that these two cardiac chymase isoforms are also expressed in the heart of TGR(hAGT)L1623 rats. In keeping with previous studies, chymase has been visualized in human (46), dog (47, 48), and enlarged rat myocytes from volume overload due to an aorto-caval fistula (21, 49). Confocal microscopy using an antibody directed to the human chymase (CMA-1) demonstrated the presence of strong chymase immunofluorescence in rats expressing the human AGT gene.…”

Section: Discussionsupporting

confidence: 86%

Activation of the Human Angiotensin-(1-12)-Chymase Pathway in Rats With Human Angiotensinogen Gene Transcripts

Ferrario

VonCannon

Ahmad

et al. 2019

Front. Cardiovasc. Med.

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Angiotensin-(1-12) [Ang-(1-12)], an alternate substrate for tissue angiotensin II (Ang II) formation, underscores the importance of alternative renin-independent pathway(s) for the generation of angiotensins. Since renin enzymatic activity is species-specific, a transgenic model of hypertension due to insertion of the human angiotensinogen (AGT) gene in Sprague Dawley rats allowed for characterizing the contribution of a non-renin dependent mechanism for Ang II actions in their blood and heart tissue. With this in mind, we investigated whether TGR(hAGT)L1623 transgenic rats express the human sequence of Ang-(1-12) before and following a 2-week oral therapy with the type I Ang II receptor (AT1-R) antagonist valsartan. Plasma and cardiac expression of angiotensins, plasma renin activity, cardiac angiotensinogen, and chymase protein and the enzymatic activities of chymase, angiotensin converting enzyme (ACE) and ACE2 were determined in TGR(hAGT)L1623 rats given vehicle or valsartan. The antihypertensive effect of valsartan after 14-day treatment was associated with reduced left ventricular wall thickness and augmented plasma concentrations of angiotensin I (Ang I) and Ang II; rat and human concentrations of angiotensinogen or Ang-(1-12) did not change. On the other hand, AT1-R blockade produced a 55% rise in left ventricular content of human Ang-(1-12) concentration and no changes in rat cardiac Ang-(1-12) levels. Mass-Spectroscopy analysis of left ventricular Ang II content confirmed a >4-fold increase in cardiac Ang II content in transgenic rats given vehicle; a tendency for decreased cardiac Ang II content following valsartan treatment did not achieve statistical significance. Cardiac chymase and ACE2 activities, significantly higher than ACE activity in TGR(hAGT)L1623 rats, were not altered by blockade of AT1-R. We conclude that this humanized model of angiotensinogen-dependent hypertension expresses the human sequence of Ang-(1-12) in plasma and cardiac tissue and responds to blockade of AT1-R with further increases in the human form of cardiac Ang-(1-12). Since rat renin has no hydrolytic activity on human angiotensinogen, the study confirms and expands knowledge of the importance of renin-independent mechanisms as a source for Ang II pathological actions.

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Section: Discussionsupporting

confidence: 86%

Activation of the Human Angiotensin-(1-12)-Chymase Pathway in Rats With Human Angiotensinogen Gene Transcripts

Ferrario

VonCannon

Ahmad

et al. 2019

Front. Cardiovasc. Med.

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“…Coculture of mast cells with cardiomyocytes promoted significant apoptosis of the cardiomyocytes (22). Additionally, it has been suggested that chymase also secreted by mast cells may induce myosin degradation within the cardiomyocytes (48). Mast cell activation with elevated histamine release has also been shown to be arrhythmogenic (58).…”

Section: Discussionmentioning

confidence: 99%

Accelerated cardiomyocyte senescence contributes to late-onset doxorubicin-induced cardiotoxicity

Mitry

Laurent

Keith

et al. 2020

American Journal of Physiology-Cell Physiology

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Children surviving cancer and chemotherapy are at risk for adverse health events including heart failure that may be delayed by years. Although the early effects of doxorubicin-induced cardiotoxicity may be attributed to a direct effect on the cardiomyocytes, the mechanisms underlying the delayed or late effects (8–20 yr) are unknown. The goal of this project was to develop a model of late-onset doxorubicin-induced cardiotoxicity to better delineate the underlying pathophysiology responsible. The underlying hypothesis was that doxorubicin-induced “late-onset cardiotoxicity” was the result of mitochondrial dysfunction leading to cell failure and death. Wistar rats, 3–4 wk of age, were randomly assigned to vehicle or doxorubicin injection groups (1–45 mg/kg). Cardiovascular function was unaltered at the lower dosages (1–15 kg/mg), but beginning at 6 mo after injection significant cardiac degradation was observed in the 45 mg/kg group. Doxorubicin significantly increased myocardial mitochondrial DNA (mtDNA) damage. In contrast, in isolated c-kit left ventricular (LV) cells, doxorubicin treatment did not increase mtDNA damage. Biomarkers of senescence within the LV were significantly increased, suggesting accelerated aging of the LV. Doxorubicin also significantly increased LV histamine content suggestive of mast cell activation. With the use of flow cytometry, a significant expansion of the c-kit and stage-specific embryonic antigen 1 cell populations within the LV were concomitant with significant decreases in the circulating peripheral blood population of these cells. These results are consistent with the concept that doxorubicin induced significant damage to the cardiomyocyte population and that although the heart attempted to compensate it eventually succumbed to an inability for self-repair.

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“…In cardiac volume overload, chymase uptake by cardiomyocytes resulted in myosin degradation and cardiomyocyte dysfunction [133]. In contrast, mast cell deficiency led to reduced contractility and myofilament Ca 2+ sensitization after myocardial infarction in mice, suggesting an important role of cardiac mast cells in preserving postischemic cardiac function [51].…”

Section: Mechanisms Of Mast Cell-mediated Effects On the Heart 71 Eff...mentioning

confidence: 99%

Mast Cells in Cardiac Remodeling: Focus on the Right Ventricle

Mamazhakypov,

Maripov,

Sarybaev

et al. 2024

JCDD

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In response to various stressors, cardiac chambers undergo structural remodeling. Long-term exposure of the right ventricle (RV) to pressure or volume overload leads to its maladaptive remodeling, associated with RV failure and increased mortality. While left ventricular adverse remodeling is well understood and therapeutic options are available or emerging, RV remodeling remains underexplored, and no specific therapies are currently available. Accumulating evidence implicates the role of mast cells in RV remodeling. Mast cells produce and release numerous inflammatory mediators, growth factors and proteases that can adversely affect cardiac cells, thus contributing to cardiac remodeling. Recent experimental findings suggest that mast cells might represent a potential therapeutic target. This review examines the role of mast cells in cardiac remodeling, with a specific focus on RV remodeling, and explores the potential efficacy of therapeutic interventions targeting mast cells to mitigate adverse RV remodeling.

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Chymase uptake by cardiomyocytes results in myosin degradation in cardiac volume overload

Cited by 13 publications

References 36 publications

Activation of the Human Angiotensin-(1-12)-Chymase Pathway in Rats With Human Angiotensinogen Gene Transcripts

Activation of the Human Angiotensin-(1-12)-Chymase Pathway in Rats With Human Angiotensinogen Gene Transcripts

Accelerated cardiomyocyte senescence contributes to late-onset doxorubicin-induced cardiotoxicity

Mast Cells in Cardiac Remodeling: Focus on the Right Ventricle

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