Ang II type 1 (AT1) receptors activate both conventional heterotrimeric G protein–dependent and unconventional G protein–independent mechanisms. We investigated how these different mechanisms activated by AT1 receptors affect growth and death of cardiac myocytes in vivo. Transgenic mice with cardiac-specific overexpression of WT AT1 receptor (AT1-WT; Tg-WT mice) or an AT1 receptor second intracellular loop mutant (AT1-i2m; Tg-i2m mice) selectively activating Gαq/Gαi-independent mechanisms were studied. Tg-i2m mice developed more severe cardiac hypertrophy and bradycardia coupled with lower cardiac function than Tg-WT mice. In contrast, Tg-WT mice exhibited more severe fibrosis and apoptosis than Tg-i2m mice. Chronic Ang II infusion induced greater cardiac hypertrophy in Tg-i2m compared with Tg-WT mice whereas acute Ang II administration caused an increase in heart rate in Tg-WT but not in Tg-i2m mice. Membrane translocation of PKCε, cytoplasmic translocation of Gαq, and nuclear localization of phospho-ERKs were observed only in Tg-WT mice while activation of Src and cytoplasmic accumulation of phospho-ERKs were greater in Tg-i2m mice, consistent with the notion that Gαq/Gαi-independent mechanisms are activated in Tg-i2m mice. Cultured myocytes expressing AT1-i2m exhibited a left and upward shift of the Ang II dose-response curve of hypertrophy compared with those expressing AT1-WT. Thus, the AT1 receptor mediates downstream signaling mechanisms through Gαq/Gαi-dependent and -independent mechanisms, which induce hypertrophy with a distinct phenotype.
Peiyong Zhai, Mitsutaka Yamamoto, Jonathan Galeotti, Jing Liu, Malthi Masurekar, Jill Thaisz, Keiichi Irie, Eric Holle, Xianzhong Yu, Sabina Kupershmidt, Dan M. Roden, Thomas Wagner, Atsuko Yatani, Dorothy E. Vatner, Stephen F. Vatner, Junichi Sadoshima
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