Mechanical Stress Triggers Cardiomyocyte Autophagy through Angiotensin II Type 1 Receptor-Mediated p38MAP Kinase Independently of Angiotensin II.

Angiotensin II (Ang II) type 1 (AT₁) receptor is known to mediate a variety of physiological actions of Ang II including autophagy. However, the role of AT₁ receptor in cardiomyocyte autophagy triggered by mechanical stress still remains elusive. The aim of this study was therefore to examine whether and how AT₁ receptor participates in cardiomyocyte autophagy induced by mechanical stresses. A 48-hour mechanical stretch and a 4-week transverse aorta constriction (TAC) were imposed to cultured cardiomyocytes of neonatal rats and adult male C57B/L6 mice, respectively, to induce cardiomyocyte hypertrophy prior to the assessment of cardiomyocyte autophagy using LC3b-II. Losartan, an AT₁ receptor blocker, but not PD123319, the AT₂ inhibitor, was found to significantly reduce mechanical stretch-induced LC3b-II upregulation. Moreover, inhibition of p38MAP kinase attenuated not only mechanical stretch-induced cardiomyocyte hypertrophy but also autophagy. To the contrary, inhibition of ERK and JNK suppressed cardiac hypertrophy but not autophagy. Intriguingly, mechanical stretch-induced autophagy was significantly inhibited by Losartan in the absence of Ang II. Taken together, our results indicate that mechanical stress triggers cardiomyocyte autophagy through AT₁ receptor-mediated activation of p38MAP kinase independently of Ang II. [ABSTRACT FROM AUTHOR]