The effects and mechanism of angiotensin (1-7) signaling on excitation-contraction coupling in diabetic cardiomyopathy

Objective: The Renin-angiotensin system (RAAS) is known to play a critical role in diabetic cardiomyopathy (DCM). Angiotensin converting enzyme 2 (ACE2) and Ang (1-7)/MasR axis, which are recognized as new players of this system, are thought to play a role in development of DCM. In this study, we have aimed that to observe possible effects of Ang (1-7), which has beneficial effects on cellular levels of cardiac pathologies, and its mechanisms on excitation-contraction coupling impaired in DCM. Method: Ang (1-7) (600 µg/kg) was administered i.p. for 30 days to Wistar rats in which experimental diabetes model was created with STZ (50 mg/kg; single dose). ECG and left ventricular pressure-volume loops were assessed to observe the changes in organ level. At cardiomyoctes level, excitation-contraction coupling was evaluated by patch-clamp and fluorometric methods. In addition, we have been evaluated that levels of local RAAS components and proteins involved in intracellular Ca2+ homeostasis to contribution on excitation-contraction coupling by using western-blot method. Results: We observed decrease in cardiac efficiency by causing diabetes impaired cardiac output, stroke volume and stroke work. Diabetes prolonged relaxation period, slowed filling rate and disrupted the the left ventricular-aorta coupling by increasing arterial elastance. Ultimately, these changes lead to diastolic dysfunction in DCM, and Ang (1-7) ameliorated these changes. The prolongation of APD due to a decrease in Ito was observed in DCM. Ang (1-7) increased Ito due to increasing K+ channel proteins and consequently prevents prolongation of APD. Diabetes disrupts the CICR mechanisms due to decreased ICaL, delayed Ca2+ intake into SR, increased diastolic [Ca2+]i and decreased Ca2+ release from RYR. Ang (1-7) protected the CICR mechanisms by improving these impairment. Ang (1-7) blocked the alteration in PKA, CaMKII and PKC function levels caused by diabetes. Ang (1-7) application improved the suppressed ACE2 activity. Conclusion: Ang (1-7) prevents diastolic dysfunction in diabetes by balancing ACE and ACE2 activity ratio. Key words: Diabetic Cardiomyopathy, Renin-Angiotensin-Aldosterone System, Angiotensin (1-7), Electrophysiology, Excitation-Contraction Coupling