Angiotensin-(1–12)/chymase axis modulates cardiomyocyte L-type calcium currents in rats expressing human angiotensinogen. (15th December 2019)

• Record Type: Journal Article
• Authors: Reyes, Santiago; Cheng, Che Ping; Roberts, Drew J.; Yamashita, Tomohisa; Ahmad, Sarfaraz; VonCannon, Jessica L.; Wright, Kendra N.; Dell'Italia, Louis J.; Varagic, Jasmina; Ferrario, Carlos M.
• Is Part Of: International journal of cardiology. Volume 297(2019)
• Page Start: 104
• Page End: 110
• Publication Date: 2019-12-15
• Subjects: Angiotensin II type 1 receptor -- Hypertension -- Hypertrophy -- Ang-(1–12) -- Ang II -- Chymase; Cardiology -- Periodicals; Electronic journals; 616.12
• DOI: 10.1016/j.ijcard.2019.09.052
• Languages: English
• ISSNs: 0167-5273

Abstract

Abstract: Background: Activation of the intracrine renin angiotensin systems (RAS) is increasingly recognized as contributing to human pathologies, yet non-canonical renin-independent mechanisms for angiotensin II (Ang II) biosynthesis remain controversial. Direct Ang II generation from angiotensin-(1–12) [Ang-(1–12)] by chymase is an essential intracrine source for regulation of cardiac function. Using a transgenic rat model that overexpresses the human angiotensinogen gene [TGR(hAGT)L1623] and displays increased cardiac Ang II levels, this study aimed to provide evidence for intracrine activation of L-type calcium currents ( I Ca-L ) mediated by the Ang-(1–12)/chymase axis. Methods and results: On patch clamp, I Ca-L density was significantly higher in TGR(hAGT)L1623 (−6.4 ± 0.3 pA/pF) compared to Sprague Dawley (SD) cardiomyocytes (−4.8, ± 0.5 pA/pF). Intracellular administration of Ang II and Ang-(1–12) elicited a I Ca-L increase in both SD and TGR(hAGT)L1623 cardiomyocytes, albeit blunted in transgenic cells. I Ca-L activation by intracellular Ang II and Ang-(1–12) was abolished by the specific Ang II type 1 receptor blocker E−3174. Co-administration of a chymase inhibitor prevented activation of I Ca-L by Ang-(1–12). Confocal micrographs revealed abundant chymase (mast cell protease 5) immunoreactive protein in SD and TGR(hAGT)L1623 cardiomyocytes. Conclusions: Our data demonstrate the existence in cardiomyocytes of a calcium channel modulatory activity responsive to Ang II generated by the Ang-(1–12)/chymase axis that signals via intracellular receptors. Chronically elevated Ang II in TGR(hAGT)L1623 hearts leading to increased intracellular calcium through I Ca-L suggests that activation of this Ang-(1–12)/chymase-governed cardiac intracrine RAS may contribute to the pathological phenotypes observed in the humanized model of chronic hypertension and cardiac hypertrophy. Highlights: Ang-(1–12)/chymase axis is active in cardiomyocytes of Ang II-mediated heart disease model. Intracellular Ang II and Ang-(1–12) control L-type calcium currents. Chymase inhibition prevents Ang-(1–12) L-type calcium channel activation. Ang II formed by Ang-(1–12)/chymase axis acts via AT1 receptors. Targeting Ang-(1–12)/chymase axis in cardiac tissue may add benefit to current care.