Deficiency of Sirtuin 3 Accentuates Angiotensin II‐Induced Arterial/Myocardial Stiffness and Hypertension

Hypertension is prevalent disease worldwide and is considered as the key factor for the development of heart failure with preserved ejection fraction (HFpEF). Arterial stiffness is the center feature of hypertension and has significant impact upon disease etiology and outcomes. Sirtuin 3 (SIRT3) emerged as a protein of particular interest to the aging and cardiovascular disease in humans. Our previous study has shown that deletion of SIRT3 resulted in impairment of coronary flow reserve (CFR) and diastolic dysfunction in mice. Little is known about role of SIRT3 in angiotensin II‐induced arterial stiffness and hypertension. In present study, wild type (WT) mice and SIRT3KO mice were infusion with Ang II (1000 ng/kg/min) for 4 weeks, blood pressure, pulse‐wave velocity (PWV), CFR and diastolic function (IVRT and MPI) were measured before and after Ang II treatment. Aorta and heart were collected and fibrosis were measured by Masson staining and fibroblast specific protein‐1 (FSP‐1) immunostaining. Our results revealed that Ang II infusion led to a significant increase in PWV, whereas knockout of SIRT3 further enhanced Ang II‐induced elevation of PWV. This was accompanied by increases in systolic, diastolic pressure and MAP in SIRT3KO mice + Ang II as compared to WT mice + Ang II. Knockout of SIRT3 further reduced CFR and increased IVRT and MPI in mice. Histologic and immunostaining studies revealed that Ang II‐induced aortic thickness and perivascular fibrosis were significantly increased in SIRT3KO mice compared to WT mice. Similarly, there were significant increase in Ang II‐induced fibrosis area and higher number of FSP‐1 + in the heart of SIRT3KO mice than WT mice. In addition, the expression of PDGF‐β was higher in the aorta and heart of SIRT3KO mice than WT mice. Double staining PDGF‐β with FSP‐1 showed an increased number of PDGF‐β + /FSP‐1 + . Using NG2 pericyte tracing reporter NG2DsRedBAC mice, we further confirmed that Ang‐II‐induced NG2 pericyte recruitment was significantly increased in the SIRT3 KO mice, suggesting deletion of SIRT3 promotes Ang‐II‐induced pericyte recruitment which may differentiate into fibrosis and contribute to increased arterial and myocardial stiffness. Our study demonstrated that deletion of SIRT3 exacerbated Ang II‐induced arterial stiffness, hypertension and diastolic dysfunction. Deletion of SIRT3 increased arteries and myocardial stiffness via enhancing pericyte recruitment and pericytes‐to‐fibroblast transition. Support or Funding Information This work was supported by R01HL102042‐06 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .