Adrenomedullin gene delivery alleviates hypertension and its secondary injuries of cardiovascular system.

Adrenomedullin (AM) is a hypotensive peptide that functions as an important regulator in the cardiovascular and renal systems. The current study explored the potential therapeutic effects of delivering the human AM cDNA via a novel double-stranded adeno-associated virus vector (dsAAV) on hypertension and related complications in spontaneously hypertensive rats (SHR). A single dose of dsAAV-AM vector administered by tail vein injection into adult SHR resulted in significant reduction of systolic blood pressure at 2 weeks after gene delivery. This effect was observed through the entire duration of the experiment period (up to 16 weeks). Administration of dsAAV-AM also resulted in a decrease in total urine microalbumin content. Left ventricle and cardiomyocyte hypertrophy, fibrosis in the heart, glomerular sclerosis, and tubular injuries in the kidney were significantly reduced. Moreover, deterioration of hemodynamic variables was prevented in treated rats, as compared with the control groups. We conclude that AAV-mediated AM delivery can render a longterm and stable reduction of hypertension and protect against renal injury and cardiac remodeling in the spontaneously hypertensive rat model. Further preclinical studies are warranted for the development of a gene therapy strategy for human hypertension.