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Blunting of estrogen modulation of cardiac cellular chymase/RAS activity and function in SHR.

ABSTRACT: The relatively low efficacy of ACE-inhibitors in the treatment of heart failure in women after estrogen loss may be due to their inability to reach the intracellular sites at which angiotensin (Ang) II is generated and/or the existence of cell-specific mechanisms in which ACE is not the essential processing pathway for Ang II formation. We compared the metabolic pathway for Ang II formation in freshly isolated myocytes (CMs) and non-myocytes (NCMs) in cardiac membranes extracted from hearts of gonadal-intact and ovariectomized (OVX) adult WKY and SHR rats. Plasma Ang II levels were higher in WKY vs. SHR (strain effect: WKY: 62?±?6?pg/ml vs. SHR: 42?±?9?pg/ml; p?

SUBMITTER: Ahmad S

PROVIDER: S-EPMC5741475 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Blunting of estrogen modulation of cardiac cellular chymase/RAS activity and function in SHR.

Ahmad Sarfaraz S Sun Xuming X Lin Marina M Varagic Jasmina J Zapata-Sudo Gisele G Ferrario Carlos M CM Groban Leanne L Wang Hao H

Journal of cellular physiology 20171004 4

The relatively low efficacy of ACE-inhibitors in the treatment of heart failure in women after estrogen loss may be due to their inability to reach the intracellular sites at which angiotensin (Ang) II is generated and/or the existence of cell-specific mechanisms in which ACE is not the essential processing pathway for Ang II formation. We compared the metabolic pathway for Ang II formation in freshly isolated myocytes (CMs) and non-myocytes (NCMs) in cardiac membranes extracted from hearts of g ...[more]

PMID: 28888034

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Blunting of cardioprotective actions of estrogen in female rodent heart linked to altered expression of cardiac tissue chymase and ACE2.

Project description:BackgroundDiastolic dysfunction develops in response to hypertension and estrogen (E2) loss and is a forerunner to heart failure (HF) in women. The cardiac renin-angiotensin system (RAS) contributes to diastolic dysfunction, but its role with respect to E2 and blood pressure remain unclear.MethodsWe compared the effects of ovariectomy (OVX) or sham surgery on the cardiac RAS, left ventricular (LV) structure/function, and systemic/intracardiac pressures of spontaneously hypertensive rats (SHRs: n = 6 intact and 6 OVX) and age-matched Wistar-Kyoto (WKY: n = 5 intact and 4 OVX) controls.ResultsWKY rats were more sensitive to OVX than SHRs with respect to worsening of diastolic function, as reflected by increases in Doppler-derived filling pressures (E/e') and reductions in myocardial relaxation (e'). This pathobiologic response in WKY rats was directly linked to increases in cardiac gene expression and enzymatic activity of chymase and modest reductions in ACE2 activity. No overt changes in cardiac RAS genes or activities were observed in SHRs, but diastolic function was inversely related to ACE2 activity.ConclusionEndogenous estrogens exert a more significant regulatory role upon biochemical components of the cardiac RAS of WKY versus SHRs, modulating the lusitropic and structural components of its normotensive phenotype.

| S-EPMC5805468 | biostudies-literature

Estrogen modulates the differential expression of cardiac myocyte chymase isoforms and diastolic function.

Project description:Chymases, a family of serine proteases with chymotryptic activity, play a significant role in cardiac angiotensin II (Ang II) formation from its substrate Ang-(1-12) in both human and rodent models. No studies, to date, have assessed the differences in enzymatic activity among these isoforms in Ang II formation, particularly in the cardiomyocyte (CM). Using PCR and DNA sequencing, we demonstrated that MCP-1, MCP-2, MCP-4, and MCP-5 mRNAs are expressed in the CM of both spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). While rMCP-1 and rMCP-5 gene transcripts were higher than that of other isoforms in both rat strains, WKY CM exhibits higher levels of rMCP-1 and rMCP-5 mRNAs compared to the SHR CM. Ovariectomy (OVX) increased the expression of rMCP-1 and rMCP-5 mRNAs in WKY. In SHR, OVX was associated with a blunted increase in rMCP-1 mRNA compared to OVX normotensive WKY. Chymase activity, measured as Ang II formation from Ang-(1-12), significantly correlated with rMCP-1 and rMCP-5 mRNA expression in both rat strains. Both rMCP-1 and rMCP-5 mRNA expressions were positively correlated with progressive diastolic dysfunction (increasing the ratio of early mitral inflow velocity-to-early mitral annular velocity, E/e') and expanding chamber dimensions or increasing left ventricular internal diameter end diastole. These data show rMCP-1 and rMCP-5 as the Ang II forming chymase isoforms participating in the loss of normal cardiac function due to OVX in rodents.

| S-EPMC6494700 | biostudies-literature

Estrogen inhibits mast cell chymase release to prevent pressure overload-induced adverse cardiac remodeling.

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| S-EPMC4289018 | biostudies-literature

A Chymase Inhibitory RNA Aptamer Improves Cardiac Function and Survival after Myocardial Infarction.

Project description:We have reported that mast cell chymase, an angiotensin II-generating enzyme, is important in cardiovascular tissues. Recently, we developed a new chymase-specific inhibitory RNA aptamer, HA28, and we evaluated the effects of HA28 on cardiac function and the mortality rate after myocardial infarction. Echocardiographic parameters, such as the left ventricular ejection fraction, fractional shortening, and the ratio of early to late ventricular filling velocities, were significantly improved by treatment with HA28 after myocardial infarction. The mortality rate was significantly reduced in the HA28-treated group. Cardiac chymase activity and chymase gene expression were significantly higher in the vehicle-treated myocardial infarction group, and these were markedly suppressed in the HA28-treated myocardial infarction group. The present study provides the first evidence that a single-stranded RNA aptamer that is a chymase-specific inhibitor is very effective in the treatment of acute heart failure caused by myocardial infarction. Chymase may be a new therapeutic target in post-myocardial infarction pathophysiology.

| S-EPMC6298900 | biostudies-literature

Autophagic activity dictates the cellular response to oncogenic RAS.

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| S-EPMC3421174 | biostudies-literature

Histone deacetylase inhibitors equipped with estrogen receptor modulation activity.

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| S-EPMC3812312 | biostudies-literature

Estrogen receptor profiling and activity in cardiac myocytes.

Project description:Estrogen signaling appears critical in the heart. However a mechanistic understanding of the role of estrogen in the cardiac myocyte is lacking. Moreover, there are multiple cell types in the heart and multiple estrogen receptor (ER) isoforms. Therefore, we studied expression, localization, transcriptional and signaling activity of ERs in isolated cardiac myocytes. We found only ER? RNA (but no ER? RNA) in cardiac myocytes using two independent methods. The vast majority of full-length ER? protein (ER?66) localizes to cardiac myocyte nuclei where it is competent to activate transcription. Alternate isoforms of ER? encoded by the same genomic locus (ER?46 and ER?36) have differential transcriptional activity in cardiac myocytes but also primarily localize to nuclei. In contrast to other reports, no ER? isoform is competent to activate MAPK or PI3K signaling in cardiac myocytes. Together these data support a role for ER? at the level of transcription in cardiac myocytes.

| S-EPMC4899180 | biostudies-literature

Myofibroblast modulation of cardiac myocyte structure and function.

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| S-EPMC6586929 | biostudies-literature

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| S-EPMC3986263 | biostudies-literature

Estrogen modulation of MgATPase activity of nonmuscle myosin-II-B filaments.

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| S-EPMC2394735 | biostudies-literature

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