Abstract 098: Blocking Cardiac Gq-Receptor Coupling Prevents Adverse Remodeling and Preserves Myocardial Function after Ischemic Injury in Mice and Promotes Repair via Cardiac Regeneration
Background: Studies have shown that the heterotrimeric G protein, Gq, is a critical molecule in the development of myocardial hypertrophy and heart failure (HF). In the present study, we examined whether Gq signaling is also a critical pathological trigger for adverse remodeling and HF after ischemic injury. Using cardiac-specific transgenic mice with expression of a specific Gq inhibitory peptide (GqI) that blocks Gq-GPCR coupling allowed us to investigate whether Gq inhibition can alter cardiac structure and functional changes after myocardial infarction (MI).
Methods and Results: Cardiac-specific GqI transgenic (TG) and non-transgenic littermate control (NLC) mice were subjected to MI. Serial echocardiography performed before ischemia as well as 2, 4, 8 weeks after MI injury show that TG mice develop less progressive LV enlargement and dysfunction. The % LV EF and FS were significantly improved in the TG compared to NLC mice at 8 weeks post-MI. Consistently, cardiac contractility (+dP/dt) and relaxation (-dP/dt) were significantly improved in TG mice also when stimulated with isoproterenol. The LVEDP, the heart weight to body weight (BW) and lung to BW ratios were significantly less in TG mice, indicating that HF was limited with GqI expression. Moreover, TG mice have smaller infarcts, less LV dimensions and lower fibrosis in both the border zone and remote area with clearly more viable tissue in the scar region. Constantly, there are more micro-vessel and more BrdU(+) cardiomyocytes in the scar area and border zone at the 2 week post-MI in TG group. Western blot shows a consistent decrease in phosphorylated PKC substrates and higher levels of activated Akt in TG mice. Over expression of the GqI in cultured H9c2 myoblasts did lead to higher level of Ki67 positive cells (38.06±2.46%) than a control group (21.78±2.64%) and FACS analysis showed that Gq inhibition increased the % of H9c2 cells in S phase and G2/M phase compared to control cells.
Conclusion: These data indicate cardiac specific Gq inhibition protects the heart against adverse LV remodeling and HF progression after MI. Mechanisms attributed to GqI expression appear to include improved myocyte survival, less fibrosis, and promotion of angiogenesis and cardiac repair through regeneration.
- © 2013 by American Heart Association, Inc.