Abstract 1577: Cardiac Specific Inhibition of Gq Signaling Improves Cardiac Function by Improving Extracellular Remodeling Following Chronic Hypertension
Hypertension (HBP) and heart failure are associated with increased plasma levels of norepinephrine and angiotensin II (AngII), which activate Gq coupled receptors. We showed that transgenic mice expressing a peptide inhibitor of Gq signaling (GqI) in vascular smooth muscle have decreased BP when infused with AngII but no cardiac hypertrophy (CH). However, when chronic HBP is induced via 2 kidney, 1 clip (2K1C) BP is decreased but CH persists. The hypothesis of this study is that cardiac specific expression of GqI will prevent CH following chronic HBP.
METHODS: Age and sex-matched GqI mice and their nontransgenic littermate controls (NLC) were 2K1C. Echo was performed pre-2K1C and at 2, 4, and 8 weeks (wks) post 2K1C. RT-PCR was performed on ventricular RNA. Cardiac myocytes were isolated and size was determined by Coulter counter (volume) and brightfield microscopy.
RESULTS: NLC and GqI 2K1C mice had significantly increased conscious BP compared to sham (122.2±5.3 and 126.8±8.5 vs. 97.5±5.8 mmHg, n=6 – 8, P<.05). Although both NLC and GqI 2K1C had decreased ejection fraction (EF) compared to sham after two wks (57.2%±3.0 and 60.2%±3.3 vs. 66.1%±1.7, n=12–18), GqI 2K1C had improved EF as compared to NLC 2K1C at 4 (59%±2 vs. 51%±2, n=18 and 15, P<.05) and 8 wks post 2K1C (53±2 vs. 44±2, n=18 and 15, P<.05) and both were significantly decreased compared to sham (4 wks: 68.6%±0.6 and 8 wks: 66.9%±2.2). Interestingly, both NLC and GqI 2K1C had similarly increased posterior wall thicknesses (PWT) compared to shams at 2 wks (0.93±.04 mm and 0.93±.07 mm vs. 0.77±.02 mm, n=12–18, P<.05), 4 wks (1.03±.04 mm and 1.00±.04 mm vs. 0.82±.02 mm, n=12–18, P<.05) and 8 wks (1.02±.04 mm and 0.92±.04 mm vs. 0.81±.02 mm, n=12–18, P<.05) post 2K1C. NLC and GqI 2K1C both had similarly increased myocyte volume (33 and 33 vs 29 fL, n=3, P<.05) and cell length (152±5 and 146±4 vs. 128±4 μm, n=3 hearts,25–30 cells/heart) versus sham. There was an increase in MMP3 mRNA expression in NLC 2K1C versus sham (6-fold±2.2, n=10, 10, P<.05) that was attenuated in GqI 2K1C (1.4-fold±0.3 vs. sham, n=9, P=NS).
CONCLUSIONS: GqI mice have improved cardiac function(CF) concomitant with CH. GqI expression appears to affect extracellular remodeling suggesting this may be the mechanism how GqI improves CF during chronic HBP.