A transgenic mouse model of heart failure using inducible Gα_q

Receptors coupled to Gα_q play a key role in the development of heart failure. Studies using genetically modified mice suggest that Gα_q mediates a hypertrophic response in cardiac myocytes. Gα_q signaling in these models is modified during early growth and development, whereas most heart failure in humans occurs after cardiac damage sustained during adulthood. To determine the phenotype of animals that express increased Gα_q signaling only as adults, we generated transgenic mice that express a silent Gα_q protein (Gα_qQ209L-hbER) in cardiac myocytes that can be activated by tamoxifen. Following drug treatment to activate Gα_qQ209L-hbER, these mice rapidly develop a dilated cardiomyopathy and heart failure. This phenotype does not appear to involve myocyte hypertrophy but is associated with dephosphorylation of phospholamban (PLB), decreased sarcoplasmic reticulum Ca²⁺-ATPase activity, and a decrease in L-type Ca²⁺ current density. Changes in Ca²⁺ handling and decreased cardiac contractility are apparent 1 week after Gα_qQ209L-hbER activation. In contrast, transgenic mice that express an inducible Gα_q mutant that cannot activate phospholipase Cβ (PLCβ) do not develop heart failure or changes in PLB phosphorylation, but do show decreased L-type Ca²⁺ current density. These results demonstrate that activation of Gα_q in cardiac myocytes of adult mice causes a dilated cardiomyopathy that requires the activation of PLCβ. However, increased PLCβ signaling is not required for all of the Gα_q-induced cardiac abnormalities.