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Alamandine enhances cardiomyocyte contractility in hypertensive rats through a nitric oxide-dependent activation of CaMKII. | LitMetric

AI Article Synopsis

  • The renin-angiotensin system (RAS) is linked to heart diseases, and alamandine, a newly discovered peptide, shows protective effects, although its exact mechanisms are not fully understood.* -
  • In a rat model of hypertension, alamandine boosts the contractile strength of heart cells by activating MrgD receptors and improves calcium regulation, which is critical for heart function.* -
  • The study reveals that alamandine stimulates nitric oxide (NO) production, which is essential for enhancing heart cell contractions through the activation of CaMKII, highlighting a potential therapeutic pathway for treating heart issues.*

Article Abstract

Overstimulation of the renin-angiotensin system (RAS) has been implicated in the pathogenesis of various cardiovascular diseases. Alamandine is a peptide newly identified as a protective component of the RAS; however, the mechanisms involved in its beneficial effects remain elusive. By using a well-characterized rat model of hypertension, the TGR (mREN2)27, we show that mREN ventricular myocytes are prone to contractile enhancement mediated by short-term alamandine (100 nmol/L) stimulation of Mas-related G protein-coupled receptor member D (MrgD) receptors, while Sprague-Dawley control cells showed no effect. Additionally, alamandine prevents the Ca dysregulation classically exhibited by freshly isolated mREN myocytes. Accordingly, alamandine treatment of mREN myocytes attenuated Ca spark rate and enhanced Ca reuptake to the sarcoplasmic reticulum. Along with these findings, KN-93 fully inhibited the alamandine-induced increase in Ca transient magnitude and phospholamban (PLN) phosphorylation at Thr17, indicating CaMKII as a downstream effector of the MrgD signaling pathway. In mREN ventricular myocytes, alamandine treatment induced significant nitric oxide (NO) production. Importantly, NO synthase inhibition prevented the contractile actions of alamandine, including PLN-Thr17 phosphorylation at the CaMKII site, thereby indicating that NO acts upstream of CaMKII in the alamandine downstream signaling. Altogether, our results show that enhanced contractile responses mediated by alamandine in cardiomyocytes from hypertensive rats occur through a NO-dependent activation of CaMKII.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191420PMC
http://dx.doi.org/10.1152/ajpcell.00153.2019DOI Listing

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