Hypertension is a major health problem in Western Societies and a risk factor for stroke, myocardial infarction, and heart failure. Blood pressure of many hypertensive patients remains poorly controlled despite treatment with multiple drugs, likely due to additional mechanisms contributing to hypertension that are unaffected by current treatments. Recently, we have defined novel role of mitochondrial superoxide (O2?) in hypertension. We have shown that genetic manipulation of mitochondrial antioxidant enzyme superoxide dismutase (SOD2) affects blood pressure. In the proposed studies, we will take this work forward by defining a new mechanism of mitochondrial dysfunction. Our preliminary data indicate that SOD2 becomes hyperacetylated due to a decline in activity of the key mitochondrial deacetylase Sirtuin 3 (Sirt3). We propose that reduced Sirt3 activity and SOD2 hyperacetylation contribute to oxidative stress and hypertension, and that measures to increase Sirt3 activity will prevent vascular dysfunction and reduce hypertension. This novel concept may lead to a paradigm-shift in defining Sirt3 as a new target in the treatment of hypertension. The overall objective of this proposal is to investigate the specific molecular mechanisms of Sirt3 impairment and SOD2 hyperacetylation, define their contribution to hypertension and to identify potential therapeutic approaches to reduce this phenomenon. We will pursue the following aims:
AIM 1. To determine the role of tissue specific Sirt3 impairment in vascular oxidative stress and hypertension. In this aim we will examine the specific roles of Sirt3 in mice with Sirt3 depletion n endothelium (EcSirt3 KO) or vascular smooth muscle (SmcSirt3 KO) in vascular oxidative stress using angiotensin II and DOCA-salt induced hypertension, and compare with Sirt3-/- and wild-type mice.
AIM 2. To determine the molecular mechanisms of reduced Sirt3 deacetylase activity and SOD2 hyper- acetylation in oxidative stress in response to angiotensin II and TNFa. Specifically, we will define the mechanisms of Sirt3 inactivation and the role of lysine acetyltransferase GCN5L1 in SOD2 hyperacetylation, O2? overproduction and impairment of endothelium dependent vasodilatation.
AIM 3. To study if Sirt3 overexpression and SOD2 mimetics reduce vascular oxidative stress and inhibit hypertension. In this aim we will test the hypothesis that genetic Sirt3 overexpression or scavenging of downstream mitochondrial O2? by new SOD2 mimetics will improve Sirt3 function, protect from vascular oxidative stress and inhibit Ang II and DOCA-salt induced hypertension. We are in an ideal position to perform these studies. We have developed unique transgenic mouse models and designed new mitochondria-targeted SOD2 mimetics to rescue vascular function in Sirt3 impairment. We have exclusive expertise in oxidative stress, hypertension, mitochondria-targeted antioxidants, mitochondrial and vascular studies. This work has the potential of providing a new understanding and treatment for this disease. Of note, our new SOD2 mimetics could be used as novel therapeutic agents in humans.
Aging is associated with increased incidence of hypertension and a decline of the mitochondrial energy regulator deacetylase Sirt3. Our data indicate that reduced Sirt3 activity occurs in hypertension due to S- glutathionylation and that this leads to SOD2 hyperacetylation and inactivation, promoting vascular oxidative stress and blood pressure elevation. In this proposal we will develop unique transgenic mouse models to determine tissue specific role of Sirt3 impairment and we will design innovative mitochondria-targeted SOD2 mimetics to rescue Sirt3 and SOD2 activity in order to treat vascular oxidative stress and reduce hypertension.
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