Abstract 5083: Klotho Gene Delivery Delays and Attenuates Spontaneous Hypertension
Background- Klotho is a recently-discovered anti-aging gene. Knockout of klotho gene shortens the lifespan while over-expression of klotho gene extends lifespan of mice. The prevalence of hypertension increases with age. Therefore, hypertension and related cardiovascular diseases are aging disorders. The expression of klotho was decreased significantly in SHRs. The purpose of this experiment was to test our hypothesis that klotho gene delivery attenuates spontaneous hypertension.
Methods and Results- Recombinant adeno-associated virus (AAV-2) carrying mouse klotho full-length cDNA (AAV.mKL) was constructed for in vivo expression of klotho. Four groups of male SHR (4 weeks) (8 rats/group) and 1 group of age-matched WKY rats (5 rats/group) were used. Blood pressure (BP) and body weight (BW) were measured twice in all animals before gene delivery in SHR. Briefly, the 4 groups of SHR received IV injection of AAV.mKL, AAV.LacZ, AAV.GFP, and PBS, respectively. The WKY group received PBS as a control. Following gene delivery, BP and BW was monitored weekly. BPs of SHR groups treated with AAV.LacZ, AAV.GFP, or PBS were significantly higher than that of the WKY group treated with PBS. AAV.mKL delayed and significantly attenuated the elevation of BP without affecting the body weight gain in SHRs. One single dose of AAV.mKL attenuated spontaneous hypertension for up to 12 weeks (length of the study). The systolic BP was 140±3.6, 174±4, and 126±2.8 mmHg for SHR-mKL, SHR-LacZ, and WKY-PBS groups, respectively. AAV.mKL also significantly increased hypotensive responses to acetylcholine, suggesting that klotho gene delivery improved endothelial function. AAV.mKL significantly decreased NADPH oxidase activity and superoxide production in mesenteric resistance arteries. Klotho gene delivery abolished renal damage in SHRs.
Conclusion- AAV delivery of mouse klotho gene delayed and attenuated hypertension in SHR. The antihypertensive effect of klotho may be mediated by inhibition of NADPH oxidases. Klotho deficiency may play a role in the development of spontaneous hypertension.
This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).