GI PROTEIN AS POTENTIAL TARGET FOR THE TREATMENT OF HYPERTENSION



Madhu B. Anand-Srivastava, Ph.D., Faculty of Medicine, University of Montreal, Montreal, QC, Canada

Guanine nucleotide regulatory proteins (G proteins) play an important role in the regulation of a variety of physiological functions including blood pressure through the activation of different effectors. We have previously shown an overexpression of inhibitory G proteins (Gialpha proteins) in spontaneously hypertensive rats (SHR) and other models of hypertensive rats. The enhanced expression of Gialpha proteins precedes the development of hypertension in SHR and DOCA-salt hypertensive rats. Treatment of prehypertensive SHR with pertussis toxin that inactivates both Gialpha-2 and Gialpha-3 proteins prevented the development of hypertension in SHR suggesting the implication of enhanced expression of Gialpha proteins in the pathogenesis of hypertension. In the present study, we investigated if both the Gialpha-2 and Gialpha-3 proteins are implicated in the development of hypertension and used the antisense (AS) approach. The knockdown of Gialpha-2 protein by Gialpha-2 AS prevented the development of hypertension up to 6 weeks of age, thereafter it started increasing and reached the same level at 9 weeks as that of untreated SHR. On the other hand, the treatment of SHR with Gialpha-3 AS did not significantly attenuate the increased BP. Furthermore, the levels of Gialpha-2 and Gialpha-3 proteins in heart, kidney and aorta from 6 week-old SHR treated with Gialpha-2-AS and Gialpha-3-AS were significantly decreased compared to control SHR. However, these treatments did not attenuate the increased BP and overexpression of Gialpha-2 and Gialpha-3 proteins in 9 week-old SHR. Furthermore, treatment of prehypertensive SHR with C-ANP4-23; an agonist of natriuretic peptide receptor-C (NPR-C) and resveratrol, attenuated the development of hypertension and overexpression of Gialpha proteins in heart and aorta. These results suggest that Gialpha-2 protein plays an important role in the development of hypertension in SHR and that the new therapies targeting Gialpha proteins may be developed for the treatment of hypertension
(Supported by grant from CIHR).