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

Ahmad, Sarfaraz; Sun, Xuming; Lin, Marina; Varagić, Jasmina; Zapata‐Sudo, Gisele; Ferrario, Carlos M.; Groban, Leanne; Wang, Hao

doi:10.1002/jcp.26179

Cited by 15 publications

(12 citation statements)

References 82 publications

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“…rMCP-1 and rMCP-5 were the predominant chymase isoforms in WKY and SHR while expression levels of all rMCPs were significantly lower in CMs from SHR. The current findings expand on our previous observation that OVX in WKY is associated with increased chymase enzymatic activity [23]through demonstrating that this effect is due to a robust increase in rMCP-1 and rMCP-5 mRNA levels in CMs of WKY. A comparatively modest increase in rMCP-1 in CMs was seen in OVX SHR, with no change in rMCP-5 with OVX.…”

Section: Discussionsupporting

confidence: 88%

“…Previous studies from our laboratory found that ovarian hormones regulate the expression and activity of cardiac rMCP-1 in the SHR [23], and that ovariectomy (OVX) augments cardiac chymase activity in both Wistar Kyoto rats (WKY) and SHR [23]. The present study was designed to identify: 1) other isoforms of rat mast cell serine proteases expressed in cardiomyocytes (CM); 2) which chymase isoforms correlate with indices of cardiac function and Ang II forming activity in the CM; and 3) the impact of ovarian hormone depletion on the expression of chymase isoforms in the CM.…”

Section: Introductionmentioning

confidence: 79%

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

et al. 2019

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Background and objective Cardiac angiotensin II (Ang II) is involved in the diastolic dysfunction in postmenopausal women. Chymases, a family of serine proteases with chymotryptic activity, play a significant role in cardiac Ang II formation from its substrate Ang‐(1–12) in both human and rodent models. While human tissue expresses only the α‐form of chymase, α‐ and β‐forms exist in rodents. Five of the ten rat mast cell proteases (rMCP‐1–5) display chymase activity, and rats express predominantly the β‐chymase isoforms. This study was designed to assess the differences in enzymatic activity among these rMCP isoforms in Ang II formation, particularly in the cardiomyocyte (CM), and the effects of estrogen status on MCP gene expression and activities in female rat models. Methods and results Using conventional polymerase chain reaction (PCR) (Fig. 1A), real‐time PCR (Fig. 1B) and DNA sequencing (Fig. 1C), 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 other isoforms in both rat strains, WKY CM exhibits higher levels of rMCP‐1 and rMCP‐5 mRNAs compared to the SHR CM (Fig. 2). 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 by HPLC 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 increases in left ventricular internal diameter end diastole. Conclusion These data show rMCP‐1 and rMCP‐5 as the Ang II forming chymase isoforms participating in diastolic dysfunction due to ovariectomy in rodents. Support or Funding Information This work was funded by grants from the National Heart Lung and Blood Institute (CMF and LG) P01‐HL051952 and the National Institute on Aging (LG) AG033727 of the National Institute of Health. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 79%

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

et al. 2019

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“…ACE2 deactivation showed a robust correlation to the diastolic dysfunctional phenotype of SHRs and a modest relationship to worsening filling pressures in WKY rats after OVX. In a follow-up study to determine the exact role of estrogen status on ACE2 in isolated cardiomyocytes [21], we again found that ACE2 activity was higher in normotensive WKY rats, although this strain effect was independent of estrogen status. Indeed, loss of ACE2 has been shown to accelerate maladaptive remodeling after MI [71].…”

Section: Estrogen Regulation Of Ace2mentioning

confidence: 70%

“…Based on the growing evidence suggesting a sex-based difference in COVID-19 outcomes, an assessment of sexspecific hormone activity, particularly estrogen, in COVID-19 pathogenesis is warranted. Estrogen is known to modulate CVD risk and we [11] and others [18] have established a role for estrogen in regulating renin-angiotensin system (RAS) expression and activity [18][19][20][21][22][23][24][25][26][27][28]. The identification of angiotensin-converting enzyme-2 (ACE2) as the host cell receptor for the SARS-CoV-1 and SARS-CoV-2 [29] coronaviruses has brought attention to the functions of this enzyme outside the domain of its now established role in modulating angiotensin II (Ang II) metabolism as part of the RAS [30].…”

Section: Introductionmentioning

confidence: 99%

Is Sex a Determinant of COVID-19 Infection? Truth or Myth?

et al. 2020

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Purpose of Review Angiotensin-converting enzyme 2 (ACE2), a specific high-affinity angiotensin II-hydrolytic enzyme, is the vector that facilitates cellular entry of SARS-CoV-1 and the novel SARS-CoV-2 coronavirus. SARS-CoV-2, which crossed species barriers to infect humans, is highly contagious and associated with high lethality due to multi-organ failure, mostly in older patients with other co-morbidities. Recent Findings Accumulating clinical evidence demonstrates that the intensity of the infection and its complications are more prominent in men. It has been postulated that potential functional modulation of ACE2 by estrogen may explain the sex difference in morbidity and mortality. Summary We review here the evidence regarding the role of estrogenic hormones in ACE2 expression and regulation, with the intent of bringing to the forefront potential mechanisms that may explain sex differences in SARS-CoV-2 infection and COVID-19 outcomes, assist in management of COVID-19, and uncover new therapeutic strategies.

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“…Total RNA was isolated from the heart using the RNeasy Lipit Tissue Mini Kit (Qiagen, Inc., Germantown, MD) and further purified using RNeasy MinElute Cleanup Kit (Qiagen, Inc., Germantown, MD) followed by quality assessment on an Agilent 2100 bioanalyzer, as described previously (18, 19). Relative quantification of mRNA levels by real-time qPCR for ACE, angiotensin converting enzyme 2 (ACE2), mast cell proteases (MCP-1, and MCP-5) was performed using a SYBR Green PCR kit (Qiagen, Inc., Germantown, MD) (19).…”

Section: Methodsmentioning

confidence: 99%

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

Cited by 15 publications

References 82 publications

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

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

Is Sex a Determinant of COVID-19 Infection? Truth or Myth?

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

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