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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

Similar Datasets

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.

Project description:RAS is frequently mutated in human cancers and has opposing effects on autophagy and tumorigenesis. Identifying determinants of the cellular responses to RAS is therefore vital in cancer research. Here, we show that autophagic activity dictates the cellular response to oncogenic RAS. N-terminal Apoptosis-stimulating of p53 protein 2 (ASPP2) mediates RAS-induced senescence and inhibits autophagy. Oncogenic RAS-expressing ASPP2((?3/?3)) mouse embryonic fibroblasts that escape senescence express a high level of ATG5/ATG12. Consistent with the notion that autophagy levels control the cellular response to oncogenic RAS, overexpressing ATG5, but not autophagy-deficient ATG5 mutant K130R, bypasses RAS-induced senescence, whereas ATG5 or ATG3 deficiency predisposes to it. Mechanistically, ASPP2 inhibits RAS-induced autophagy by competing with ATG16 to bind ATG5/ATG12 and preventing ATG16/ATG5/ATG12 formation. Hence, ASPP2 modulates oncogenic RAS-induced autophagic activity to dictate the cellular response to RAS: to proliferate or senesce.

| S-EPMC3421174 | biostudies-literature

Histone deacetylase inhibitors equipped with estrogen receptor modulation activity.

Project description:We describe a set of novel histone deacetylase inhibitors (HDACi) equipped with either an antagonist or an agonist of the estrogen receptor (ER) to confer selective activity against breast cancers. These bifunctional compounds potently inhibit HDAC at nanomolar concentrations and either agonize or antagonize ERα and ERβ. The ER antagonist activities of tamoxifen-HDACi conjugates (Tam-HDACi) are nearly identical to those of tamoxifen. Conversely, ethynyl-estradiol-HDACi conjugates (EED-HDACi) have attenuated ER agonist activities relative to the parent ethynyl-estradiol. In silico docking analysis provides structural basis for the trends of ER agonism/antagonism and ER subtype selectivity. Excitingly, lead Tam-HDACi conjugates show anticancer activity that is selectively more potent against MCF-7 (ERα positive breast cancer) compared to MDA-MB-231 (triple negative breast cancer), DU145 (prostate cancer), or Vero (noncancerous cell line). This dual-targeting approach illustrates the utility of designing small molecules with an emphasis on cell-type selectivity, not merely improved potency, working toward a higher therapeutic index at the earliest stages of drug development.

| 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 ERα RNA (but no ERβ RNA) in cardiac myocytes using two independent methods. The vast majority of full-length ERα protein (ERα66) localizes to cardiac myocyte nuclei where it is competent to activate transcription. Alternate isoforms of ERα encoded by the same genomic locus (ERα46 and ERα36) have differential transcriptional activity in cardiac myocytes but also primarily localize to nuclei. In contrast to other reports, no ERα isoform is competent to activate MAPK or PI3K signaling in cardiac myocytes. Together these data support a role for ERα at the level of transcription in cardiac myocytes.

| S-EPMC4899180 | biostudies-literature

Myofibroblast modulation of cardiac myocyte structure and function.

Project description:After myocardial infarction, resident fibroblasts (Fb) differentiate towards myofibroblasts (MyoFb), generating the scar tissue and the interstitial fibrosis seen in the adjacent myocardium. Fb and MyoFb have the potential to interact with cardiac myocytes (CMs) but insight into the phenotype-specific role and mode of interaction is still incomplete. Our objectives are to further define the modulation of CMs by MyoFbs compared to Fbs, as well as the role of direct contact through gap junctions vs. soluble mediators, using Fbs and CMs from pig left ventricle. Fbs were treated to maintain an undifferentiated state (SD-208) or to attain full differentiation to MyoFb (TGF-β1). Fbs and MyoFbs were co-cultured with CMs, with the possibility of direct contact or separated by a Thincert membrane. Only in direct co-culture, both Fbs and MyoFbs were able to decrease CM viability after 2 days. Only MyoFbs induced significant distal spreading of CMs in both direct and indirect co-culture. MyoFbs, but not Fbs, readily made connections with CMs in direct co-culture and connexin 43 expression in MyoFb was higher than in Fb. When coupled to CMs, MyoFbs reduced the CM action potential duration and hyperpolarized the CM resting membrane potential. Uncoupling reversed these effects. In conclusion, MyoFbs, but not Fbs, alter the CM structural phenotype. MyoFbs, but not Fbs, are likely to electrically connect to CMs and thereby modulate the CM membrane potential. These data provide further support for an active role of MyoFbs in the arrhythmogenic substrate after cardiac remodelling.

| S-EPMC6586929 | biostudies-literature

Modulation of nuclear receptor function by cellular redox poise.

Project description:Nuclear receptors (NRs) are ligand-responsive transcription factors involved in diverse cellular processes ranging from metabolism to circadian rhythms. This review focuses on NRs that contain redox-active thiol groups, a common feature within the superfamily. We will begin by describing NRs, how they regulate various cellular processes and how binding ligands, corepressors and/or coactivators modulate their activity. We will then describe the general area of redox regulation, especially as it pertains to thiol-disulfide interconversion and the cellular systems that respond to and govern this redox equilibrium. Lastly, we will discuss specific examples of NRs whose activities are regulated by redox-active thiols. Glucocorticoid, estrogen, and the heme-responsive receptor, Rev-erb, will be described in the most detail as they exhibit archetypal redox regulatory mechanisms.

| S-EPMC3986263 | biostudies-literature

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

Project description:The study tested the hypothesis that estrogen controls epithelial paracellular resistance through modulation of myosin. The objective was to understand how estrogen modulates nonmuscle myosin-II-B (NMM-II-B), the main component of the cortical actomyosin in human epithelial cervical cells. Experiments used human cervical epithelial cells CaSki as a model, and end points were NMM-II-B phosphorylation, filamentation, and MgATPase activity. The results were as follows: 1) treatment with estrogen increased phosphorylation and MgATPase activity and decreased NMM-II-B filamentation; 2) estrogen effects could be blocked by antisense nucleotides for the estrogen receptor-alpha and by ICI-182,780, tamoxifen, and the casein kinase-II (CK2) inhibitor, 5,6-dichloro-1-beta-(D)-ribofuranosylbenzimidazole and attenuated by AG1478 and PD98059 (inhibitors of epithelial growth factor receptor and ERK/MAPK) but not staurosporine [blocker of protein kinase C (PKC)]; 3) treatments with the PKC activator sn-1,2-dioctanoyl diglyceride induced biphasic effect on NMM-II-B MgATPase activity: an increase at 1 nm to 1 microM and a decrease in activity at more than 1 microM; 4) sn-1,2-dioctanoyl diglyceride also decreased NMM-II-B filamentation in a monophasic and saturable dose dependence (EC(50) 1-10 microM); 5) when coincubated directly with purified NMM-II-B filaments, both CK2 and PKC decreased filamentation and increased MgATPase activity; 6) assays done on disassembled NMM-II-B filaments showed MgATPase activity in filaments obtained from estrogen-treated cells but not estrogen-depleted cells; and 7) incubations in vitro with CK2, but not PKC, facilitated MgATPase activity, even in disassembled NMM-II-B filaments. The results suggest that estrogen, in an effect mediated by estrogen receptor-alpha and CK2 and involving the epithelial growth factor receptor and ERK/MAPK cascades, increases NMM-II-B MgATPase activity independent of NMM-II-B filamentation status.

| S-EPMC2394735 | biostudies-literature

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