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Angiotensin-(1-12)/chymase axis modulates cardiomyocyte L-type calcium currents in rats expressing human

Santiago Reyes1, Che Ping Cheng2, Drew J Roberts1

  • 1Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA.

International Journal of Cardiology
|October 21, 2019
PubMed
Abstract

Insights

This study shows that the Angiotensin-(1-12)/chymase pathway activates cardiac L-type calcium currents. This intracrine renin-angiotensin system (RAS) activation in cardiomyocytes may contribute to hypertension and cardiac hypertrophy.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Renin-Angiotensin System Research

Background:

  • Non-canonical, renin-independent mechanisms for angiotensin II (Ang II) biosynthesis are increasingly implicated in human pathologies.
  • Direct Ang II generation from angiotensin-(1-12) [Ang-(1-12)] by chymase is a critical intracrine pathway for cardiac function regulation.

Purpose of the Study:

  • To investigate the role of the Ang-(1-12)/chymase axis in the intracrine activation of L-type calcium currents (ICa-L).
  • To provide evidence for this pathway in a transgenic rat model with elevated cardiac Ang II levels.

Main Methods:

  • Utilized a transgenic rat model overexpressing the human angiotensinogen gene [TGR(hAGT)L1623].
  • Performed patch-clamp electrophysiology to measure ICa-L density and responses to Ang II and Ang-(1-12).
  • Employed chymase inhibitors and Ang II type 1 receptor blockers (E-3174); utilized confocal microscopy for chymase localization.

Main Results:

  • TGR(hAGT)L1623 cardiomyocytes exhibited significantly higher ICa-L density compared to Sprague Dawley controls.
  • Intracellular Ang II and Ang-(1-12) increased ICa-L in both cell types, an effect blocked by E-3174.
  • Chymase inhibition abolished Ang-(1-12)-induced ICa-L activation, and chymase was detected in cardiomyocytes.

Conclusions:

  • Demonstrated cardiomyocyte calcium channel modulation via Ang II generated by the Ang-(1-12)/chymase axis, signaling through intracellular receptors.
  • Chronic Ang II elevation in TGR(hAGT)L1623 hearts increases intracellular calcium via ICa-L.
  • This Ang-(1-12)/chymase-governed intracrine RAS activation may contribute to pathological phenotypes in hypertension and cardiac hypertrophy models.
Keywords:
Ang IIAng-(1–12)Angiotensin II type 1 receptorChymaseHypertensionHypertrophy

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