Mitochondrial Deacetylase Sirt3 Reduces Vascular Dysfunction and Hypertension While Sirt3 Depletion in Essential Hypertension Is Linked to Vascular Inflammation and Oxidative Stress

Abstract

Rationale: Hypertension represents a major risk factor for stroke, myocardial infarction, and heart failure and affects 30% of the adult population. Mitochondrial dysfunction contributes to hypertension, but specific mechanisms are unclear. The mitochondrial deacetylase Sirt3 (Sirtuin 3) is critical in the regulation of metabolic and antioxidant functions which are associated with hypertension, and cardiovascular disease risk factors diminish Sirt3 level. Objective: We hypothesized that reduced Sirt3 expression contributes to vascular dysfunction in hypertension, but increased Sirt3 protects vascular function and decreases hypertension. Methods and Results: To test the therapeutic potential of targeting Sirt3 expression, we developed new transgenic mice with global Sirt3OX (Sirt3 overexpression), which protects from endothelial dysfunction, vascular oxidative stress, and hypertrophy and attenuates Ang II (angiotensin II) and deoxycorticosterone acetate–salt induced hypertension. Global Sirt3 depletion in Sirt3 −/− mice results in oxidative stress due to hyperacetylation of mitochondrial superoxide dismutase (SOD2), increases HIF1α (hypoxia-inducible factor-1), reduces endothelial cadherin, stimulates vascular hypertrophy, increases vascular permeability and vascular inflammation (p65, caspase 1, VCAM [vascular cell adhesion molecule-1], ICAM [intercellular adhesion molecule-1], and MCP1 [monocyte chemoattractant protein 1]), increases inflammatory cell infiltration in the kidney, reduces telomerase expression, and accelerates vascular senescence and age-dependent hypertension; conversely, increased Sirt3 expression in Sirt3OX mice prevents these deleterious effects. The clinical relevance of Sirt3 depletion was confirmed in arterioles from human mediastinal fat in patients with essential hypertension showing a 40% decrease in vascular Sirt3, coupled with Sirt3-dependent 3-fold increases in SOD2 acetylation, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity, VCAM, ICAM, and MCP1 levels in hypertensive subjects compared with normotensive subjects. Conclusions: We suggest that Sirt3 depletion in hypertension promotes endothelial dysfunction, vascular hypertrophy, vascular inflammation, and end-organ damage. Our data support a therapeutic potential of targeting Sirt3 expression in vascular dysfunction and hypertension.

AIBP protects retinal ganglion cells against neuroinflammation and mitochondrial dysfunction in glaucomatous neurodegeneration

“…Our study demonstrated that loss of AIBP significantly reduced the expression levels of SIRT3 and SOD2 proteins in the inner retina including RGCs. Recent evidence indicates that the SIRT3-SOD2 pathway is linked to inflammation and oxidative stress [ 75 , 76 ]. In line with these and our findings, it is possible that mitochondrial AIBP may contribute to the stabilization of the SIRT3-SOD2 axis, rescuing RGC mitochondria from neuroinflammation and/or oxidative stress.…”

The Role of microRNAs in Metabolic Syndrome-Related Oxidative Stress

“…There are numerous studies which reported persistently increased ROS levels in HT, along with vast improvement upon antioxidative treatment [121][122][123][124][125][126][127]. HT is connected with vascular remodeling, increased vasoconstriction and arterial stiffness, activation of immune cells, renal dysfunction, and excitation of sympathetic nervous system.…”

Targeting Molecular Mechanism of Vascular Smooth Muscle Senescence Induced by Angiotensin II, A Potential Therapy via Senolytics and Senomorphics

“…Soluble Klotho, an antiaging hormone, attenuates AngII-induced VSMC senescence through Nrf2 induction and ROS attenuation [79]. Mitochondrial Sirt3 also protects against mtROS [76,80]. In addition, reduction in NAD + exaggerates AngII-induced vascular senescence [76,81].…”

“…Mitochondrial Sirt3 protects against oxidative stress by promoting deacetylation of mitochondrial superoxide dismutase, SOD2. Importance of mitochondrial-derived ROS in vascular oxidative stress and senescence has been confirmed with mitochondrial Sirt3 deficient mice and Sirt3 transgenic mice infused with AngII [80]. Generation of NAD + via nicotinamide phosphoribosyl transferase (Nampt) is known to mediate cell vitality.…”