Abstract 1623: Cardiac Expression of an Intracellular Gαq Inhibitor Preserves Cardiac Function and Reduces Apoptosis Following Ischemia and Reperfusion Injury in Mice
BACKGROUND: Recent studies have demonstrated that the heterotrimeric G protein, Gαq, is a critical signaling molecule in the development of myocardial hypertrophy and heart failure (HF). Inhibition of Gq signaling reduces pressure-overload hypertrophy and prevent cardiac dysfunction and HF chronically. In the present study, we examined the role of a Gαq inhibitory peptide (GqI) in myocardial ischemia and ischemia reperfusion (I/R) models.
METHODS: GqI transgenic (TG) and non-transgenic control (NLC) mice were subjected to I/R (30min/24h) or ischemia only (4 months). At the appropriate time points cardiac function (echocardiography and hemodynamics), myocardial infarction size and myocardial apoptosis were measured.
RESULTS: Serial echocardiography was performed in NLC and TG mice before ischemia as well as 2, 4, 8, and 16 weeks after injury. NLC mice developed progressive left ventricular (LV) enlargement and dysfunction. The LV ejection fraction and fractional shortening were significantly reduced to 14.8% and 4.5% in NLC mice vs. 29.69% and 14.27% in the TG group at 4 months post-ischemia (p<0.01). Consistent with the echocardiography data, cardiac contractile function (LV dP/dt) was significantly reduced in NLC mice compared to TG mice when stimulated with isopreterenol (p<0.05). The LV end diastolic pressure as well as the heart to body weight and lung to body weight ratios were significantly higher in NLC mice, indicating end-stage HF. Moreover, myocardial infarction size was significantly increased in NLC mice (40.65±1.71%) compared to TG group (25.71±1.46). Consistently, following I/R, apoptosis was significantly reduced (50%; p<0.05) in TG vs. NLC as assessed by TUNEL staining.
CONCLUSION: These data indicate cardiac GqI expression and subsequent class-specific Gq inhibition protects the heart against ischemic injury and chronically can improve cardiac function post-ischemia.