Reversible Heart Failure in Gαq Transgenic Mice

Abstract

For many patients with cardiac insufficiency, the disease progresses inexorably to organ dilatation, pump failure, and death. Although there are examples of reversible heart failure in man, our understanding of how the myocardium repairs itself is limited. A well defined animal model of reversible heart failure would allow us to better investigate these restorative processes. Receptors that activate G␣ q , a signal transduction molecule in the heterotrimeric G protein superfamily, are thought to play a key role in the development of heart failure. We demonstrated previously that mice expressing a recombinant G␣ q protein, the activity of which can be turned on or off at will in cardiac myocytes, develop a dilated cardiomyopathy with generalized edema and heart failure following activation of the protein (Fan, G., Jiang, Y. 280, 40337-40346).Here we report that the contractile dysfunction and pathological structural changes in the myocardium improved significantly after termination of the G␣ q signal, even in animals with overt heart failure. Abnormalities in two proteins that regulate Ca 2؉ handling in myocytes, phospholamban and the voltage-dependent L-type Ca 2؉ channel, were also reversed, as was the increased expression of genes that are associated with heart failure. These results indicate that the heart has a substantial reparative capacity if the molecular signals responsible for the myocardial dysfunction can be identified and blocked.Following cardiac injury, activation of G␣ q -coupled receptors in the heart exerts deleterious effects that promote the development of heart failure. To better investigate the role of G␣ q activation in the development of cardiac failure in adult animals, we developed transgenic mice that express a recombinant G␣ q protein, the activity of which can be turned on or off at will. Fusing a mutant hormone-binding domain of the estrogen receptor (hbER) 2 to the carboxyl terminus of constitutively active G␣ q Q209L renders this G␣ q protein inactive (1). However, in the presence of 4-hydroxytamoxifen, the G␣ q Q209L-hbER (QL) protein becomes active. This inducible model allowed us to investigate the consequences of G␣ q activation in myocytes after completion of normal development and growth. We found that tamoxifen activation of the QL protein in adult transgenic mice causes a dilated cardiomyopathy that leads to heart failure (1). Heart failure is often associated with depressed cardiac contractility, which is also exhibited by the QL mice (1). Contractility of cardiac myocytes is regulated by changes in the intracellular Ca 2ϩ concentration. Ca 2ϩ enters the cell through the L-type voltage-dependent Ca 2ϩ channel (LTCC) and induces a large release of Ca 2ϩ from the sarcoplasmic reticulum (SR) through the ryanodine receptor, resulting in myocyte contraction. Relaxation is caused by removal of Ca 2ϩ either by the SR Ca 2ϩ -ATPase (SERCA) or the Na ϩ -Ca 2ϩ exchanger located at the plasma membrane. SERCA is regulated by phospholamban (PLB), which inhibits SERCA when dephospho...

Activation of Gαq in Cardiomyocytes Increases Vps34 Activity and Stimulates Autophagy

“…2). However, consistent with our previous results (14, 22, 24), mice injected for 7 days showed a significant but moderate decrease in fractional shortening (50.4% ± 1.2 before vs. 35.7% ± 2.7 after; Fig. 2).…”

“…Our Gα q Q209L mice exhibit relatively mild contractile dysfunction after 7 days of tamoxifen injections that develops into heart failure with 2–3 weeks of further treatment (14, 22). We found that autophagy was significantly increased in mice treated for 7 days, well before the onset of heart failure.…”

“…Heart failure occurred after 21–28 days of tamoxifen treatment (14, 22). WT mice did not develop abnormal cardiac contractility, even after 28 days of tamoxifen injections (14, 24).…”

“…Generation and characterization of the transgenic mouse models of inducible Gα q activation in the C57BL/6J background (termed Gα q Q209L and Gα q Q209L-AA) were described previously (14, 22–24). All protocols for animal experiments were approved by the Stony Brook University Animal Care and Use Committee.…”

“…However, direct evidence that Gα q impacts autophagy in the heart has not been reported. In this study, we used our transgenic mouse model of inducible Gα q to address this question (14, 22–24). We observed that Gα q activation in cardiac myocytes leads to increased formation of the autophagy initiation complex and thus stimulates autophagic activity prior to the onset of heart failure.…”