Abstract 046: Induction Of Endothelial Sirt3 After Onset Of Hypertension Rescues Endothelial Function

Abstract

Endothelial dysfunction plays a key role in the pathogenesis of hypertension and represents a major risk factor for cardiovascular disease. Despite treatment with multiple drugs, only 1 in 4 patients has blood pressure under control. We discovered a new synergistic control point with the potential to address this problem. We have shown that Sirt3 level is reduced in essential hypertension and endothelial Sirt3 overexpression attenuates endothelial dysfunction and hypertension. We proposed that induction endothelial Sirt3 after onset of hypertension rescues endothelial function and reduces hypertension. To test this hypothesis, we used genetic- and pharmacological Sirt3 induction. To genetically induce the expression of endothelial Sirt3 we used Sirt3 flox/flox mice crossed with VeCad-Cre mice treated with low dose of 4-hydroxytamoxifen (4HOT, i.p. 0.3 mg/20 g daily, 5 days) which does not have off-target cardiovascular effects. Mice underwent telemetry placement and ten days later received 4-week osmotic pumps containing vehicle (saline) or angiotensin II (0.7 mg/kg/day). 14-days later half of mice received 4HOT to induce endothelial Sirt3 overexpression. Treatment of mice with 4HOT after onset of hypertension slightly reduced blood pressure but most importantly completely rescued endothelial-dependent relaxation, normalized mitochondrial O 2 . - and restored endothelial nitric oxide. Second, we tested if pharmacological induction of Sirt3 by hexafluoro (i.p. 8 mg/kg, 4 days) after onset of angiotensin II-induced hypertension improves endothelial function and reduces hypertension. It was found that hexafluoro substantially reduced systolic blood pressure, significantly diminished vascular mitochondrial O 2 . - and improved endothelial nitric oxide. To test the role of endothelial Sirt3 in pharmacological effect of hexafluoro we used endothelial specific Sirt3 knockout mice and angiotensin II model of hypertension. Interestingly, hexafluoro was not effective in endothelial Sirt3 deficient mice supporting critical role of endothelial Sirt3. These in vivo studies demonstrate therapeutic potential of genetic and pharmacological endothelial Sirt3 induction after onset of hypertension for treatment of endothelial dysfunction.