Hyperacetylation of CypD Contributes to Mitochondrial Dysfunction, Vascular Oxidative Stress and Hypertension, and Mitochondria-Targeted Isoketal Scavenger mito2HOBA Prevents CypD Hyperacetylation and Reduces Hypertension.

One third of adult population has hypertension and third of hypertensive patients remain hypertensive despite treatment with multiple drugs. There have been no mechanistically novel treatments for hypertension in the past 30 years. We propose that new agents targeting CypD activation, a regulatory subunit of mitochondrial permeability transition pore, could add to the currently available therapeutic armamentarium to improve treatment of hypertension. To test this hypothesis we have studied CypD acetylation which was associated with CypD activation. We found that angiotensin II-induced hypertension is linked to CypD-K166 hyperacetylation, mPTP opening, impaired mitochondrial respiration and reduced kidney ATP. CypD hyperacetylation may result from imbalance between GCN5L1 acetyltransferase and reduced Sirt3 deacetylase activity. Indeed, aortic mitochondrial level of GCN5L1 increased by 50% while Sirt3 was reduced by 40% in angiotensin II infused mice. Sirt3 can be inactivated by cytotoxic reactive lipid dicarbonyls derived from arachidonic acid, isoketals, leading to mitochondrial hyperacetylation. To test the role of mitochondrial isoketals we synthesized a novel mitochondria-targeted isoketal scavenger mito2HOBA. mito2HOBA supplementation in drinking water (0.1g/Liter) attenuates angiotensin II-induced hypertension, prevents accumulation of mitochondrial isoketal protein adducts in the aorta and kidney measured by LC/MS and D11 antibody, improves Sirt3/GCNL1 ratio, normalizes the CypD acetylation, attenuates mPTP opening, protects mitochondrial respiration and preserves normal kidney ATP level. Decreased NO bioavailability is a hallmark of endothelial oxidative stress in hypertension due to superoxide overproduction and NO oxidation. Interestingly, angiotensin II increases vascular superoxide by 2-fold and reduces endothelial NO level to 50% while mito2HOBA diminishes vascular O 2 • and preserves NO bioavailability in angiotensin II-infused mice. These data support the role of isoketals-mediated CypD hyperacetylation in endothelial dysfunction and hypertension. We conclude that scavenging of mitochondrial isoketals may have therapeutic potential in treatment of hypertension and target-organ-damage.