Abstract 666: The G-protein Regulator Phosducin is Essential for Sympathetic Control of Blood Pressure
Hypertension and its complications represent and contribute to the leading causes of morbidity and mortality. In order to identify hypertension-associated genes, we applied a candidate gene-based association analysis in two ethnically divergent populations, of French-Canadian and African-American origin. We found that two genes located in one block of linkage disequilibrium encoding for phosducin and cyclooxygenase 2 (Cox2) were significantly associated with both basal and stress response blood pressure phenotypes. Phosducin is expressed in retina and pineal gland but has not been reported to affect the cardiovascular sytem. Thus, in order to investigate whether phosducin may independently of Cox2 contribute to the genetics of hypertension, we generated phosducin-deficient mice. The gene encoding phosducin (Pdc) was disrupted by homologous recombination in embryonic stem cells and Pdc−/ − were generated. Pdc-deficient mice could not be distinguished from wild-type littermates with respect to appearance, body weight, fertility and viability suggesting that phosducin is not essential for normal embryonic development and postnatal growth. Upon invasive hemodynamic evaluation with a microtip catheter, aortic systolic and diastolic pressures were >30 mm Hg higher in Pdc−/ − mice (systolic pressure Pdc−/ − 126.4 ± 4.3 mm Hg vs. Pdc+/+ 89.8 ± 2.0 mm Hg, p<0.05). Similar results were obtained with telemetric blood pressure monitoring. Whereas differences in resting blood pressure between Pdc−/ − and Pdc+/+ were attenuated during the day, arterial pressure remained significantly higher in Pdc−/ − mice at night. Plasma norepinephrine levels were 3.4-fold higher in Pdc−/ − than in Pdc+/+ mice, while the concentration of circulating epinephrine was not altered. Sympathetic neurons isolated from superior cervical ganglia of Pdc−/ − mice showed prolonged action potential firing and delayed desensitization of nicotinic currents as compared with Pdc+/+ neurons. Furthermore, hypertension in Pdc−/ − mice led to significant smooth muscle cell hypertrophy in muscular arteries. Taken together, these data identify phosducin as a novel regulator of sympathetic control of blood pressure and defects in this gene result in experimental hypertension.