Abstract P219: Role of Angiotensin Type I Receptor and β1 Integrin in Stretch-Induced Activation of Akt and JNK in Cardiac Myocytes
Cardiac hypertrophy is a common response to mechanical stimuli, such as increased hemodynamic load and exercise. However, the underlying mechanotransduction processes are poorly understood. Recent studies indicate that both β1 integrin and angiotensin type I receptor (AT1R) can serve as mechanoreceptors in the intact myocardium and isolated cardiac myocytes. Mechanical stress induced activation of Akt and JNK has been associated with various aspects of hypertrophic growth. We used primary cultures of NRVM plated on deformable membranes to test whether static stretch-induced activation (phosphorylation) of Akt and JNK involves β1 integrin and/or AT1R. In these studies, pretreatment with the AT1R antagonist Losartan (10 µM), significantly decreased mechanical stretch induced activation of Akt (Akt473, 47.1 ± 6.1%, p<0.01 and Akt308, 33.1 ± 3.2%, p<0.01, n=5), but not JNK after 15 min, compared to stretch alone. Although expression of dominant-negative β1D-integrin (Tac-β1D) alone had no effect on stretch-induced Akt and JNK activation, the addition of Losartan to the culture medium decreased stretch-induced activation of both Akt (Akt473, 74.9 ± 10.4%, p<0.01 and Akt308, 66.1 ± 8%, p<0.01, n=5) and JNK (60.1 ± 2.5%, p<0.01, n=5), compared to stretch in lacZ expressing cells. Because Rac1 is known to be activated by mechanical stretch in NRVM, we determined whether Rac1 is required for stretch-induced Akt and JNK activation. Adenovirus-mediated expression of dominant-negative Rac1 decreased mechanical stretch induced activation of Akt (Akt473, 36.3 ± 7.6%, p<0.05 and Akt308, 29.8 ± 6.2%, p<0.05, n=5), but not JNK. Whereas, in NRVM expressing dominant-negative Rac1, Losartan pretreatment further decreased stretch-induced activation of both Akt (Akt473, 64.9 ± 10.4%, p<0.05 and Akt308, 50.8 ± 7.8%, p<0.01, n=5) and JNK (66.7 ± 11%, p<0.05, n=5). In summary, Akt activation in acutely stretched NRVM was mediated through the AT1R, whereas JNK activation could be mediated through either AT1R or β1 integrin. The regulation Akt and JNK was also found to be significantly dependent on Rac1 activation. In conclusion, this study suggests that both AT1R and β1 integrin are important mechanosensors that activate pathways that lead to cardiac myocyte hypertrophy.
- © 2011 by American Heart Association, Inc.