Abstract 3740: Tetrahydrobiopterin Rescues Mice Lacking Beta-3 Adrenergic Receptors From Adverse Cardiac Remodeling Following Pressure Overload
Beta-3 adrenergic receptor (B3-AR) signaling in the cardiovascular system has a depressant effect on ventricular contractility, antagonizing the stimulatory role traditionally ascribed to B1/2 AR’s. Via NOS dependent increases in NO availability, B3 AR activation may induce an adaptive braking response to excess catecholamine stimulation in failing hearts. We recently presented data revealing impaired cardiac compensation and increased NOS derived superoxide in B3/mice after 9 weeks of mild transverse aortic constriction (TAC). The reducing agent and essential NOS cofactor, tetrahydrobiopterin (BH4), maintains functional coupling of NOS and NO generating catalytic activity. We therefore hypothesized that treatment with BH4 would preserve cardiac function and reduce hypertrophy in B3/mice after TAC. After 3 weeks of mild (25G needle) TAC, there was a trend towards impaired fractional shortening (−16±5%) and increased LV mass (+82±14%) in B3/vs. WT mice by echocardiography. At 3 weeks, there was a 39% increase in NOS dependent superoxide production over baseline (P<0.05), whereas NOS dependent superoxide was undetectable in WT mice with or without mild TAC. Overall cardiac NOS activity was unchanged by arginine to citrulline conversion; however, nNOS and iNOS protein levels were increased in response to TAC in B3/mice (P<0.05 for both). Total BH4 levels revealed no absolute difference between B3/and WT, and although the BH4/(BH2+B) ratio was lower in B3/mice, it was unchanged with TAC. However, 3 weeks of BH4 treatment completely abolished the increase in NOS dependent superoxide and rescued B3/mice from cardiac hypertrophy and impaired fractional shortening vs. WT. Taken together, these results implicate NOS derived superoxide in the exaggerated adverse cardiac remodeling that occurs after TAC in mice lacking B3 AR, and that reduction of this superoxide by BH4 reduces hypertrophy and preserves myocardial systolic function.