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

  • Hao WangEmail author
  • Xuming Sun
  • Sarfaraz Ahmad
  • Jing Su
  • Carlos Maria Ferrario
  • Leanne Groban
Article
  • 45 Downloads

Abstract

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.

Keywords

Mast cell protease Chymase Cardiomyocyte Hypertension Ovariectomy Angiotensin-(1-12) 

Notes

Acknowledgements

We thank Marina Lin for her technical assistance.

Funding

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.

Compliance of ethical standards

Conflict of interest

Authors declare that there are no competing interests associated with the manuscript.

Research involving human participants and/or animals

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of AnesthesiologyWake Forest School of MedicineWinston-SalemUSA
  2. 2.Department of Internal Medicine-Molecular MedicineWake Forest School of MedicineWinston-SalemUSA
  3. 3.Department of SurgeryWake Forest School of MedicineWinston-SalemUSA
  4. 4.Division of Public Health Sciences, Department of Biostatistical SciencesWake Forest School of MedicineWinston-SalemUSA
  5. 5.Department of Physiology and PharmacologyWake Forest School of MedicineWinston-SalemUSA
  6. 6.Division of Public Health Sciences, Department of Social Sciences and Health PolicyWake Forest University School of MedicineWinston-SalemUSA

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