Heterotrimeric g proteins in heart failure

Structural remodeling of the heart, including myocardial hypertrophy and fibrosis, is a key determinant for the clinical outcome of heart failure. A variety of evidence indicates the importance of neurohumoral factors, such as endothelin-1, angiotensin II, and norepinephrine for the initial phase of the development of cardiac remodeling. These agonists stimulate seven transmembrane spanning receptors that are coupled to heterotrimeric GTP-binding proteins (G proteins) of the Gi, Gq and G12 subfamilies. The pathophysiological roles of each G protein-mediated signaling have been revealed by studies using transgenic and knockout mice. Using specific pharmacological tools to assess the involvement of G protein signaling pathways, we have found that diacylglycerolactivated transient receptor potential canonical (TRPC) channels (TRPC3 and TRPC6), one of the downstream effectors regulated by Gα_q, work as a key mediator in the development of cardiac hypertrophy. In contrast, we also revealed that activation of Gα₁₂ family proteins in cardiomyocytes mediates pressure overload-induced cardiac fibrosis. Stimulation of purinergic P2Y6 receptors by extracellular nucleotides released by mechanical stretch is a trigger of Gα₁₂-mediated fibrotic responses of the heart. Although cardiac fibrosis is believed to accompany with Gα_qmediated pathological hypertrophy that eventually results in heart failure, our results clearly show that cardiac fibrosis and hypertrophy are independent processes. These findings will provide a new insight into the molecular mechanisms underlying pathogenesis of heart failure.