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Ablation of SIRT3 causes coronary microvascular dysfunction and impairs cardiac recovery post myocardial ischemia.

Abstract：

RATIONALE:Sirtuin (SIRT3), a major nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase in mitochondria, declines with aging and its ablation is associated with accelerated development of cardiovascular diseases. However, the role of SIRT3 in coronary microvascular function and post-MI recovery has not been completely understood. OBJECTIVE:The goal was to investigate whether ablation of SIRT3 causes coronary microvascular dysfunction, exacerbates post-myocardial ischemia (MI) cardiac dysfunction and impairs cardiac recovery. METHODS AND RESULTS:Using endothelial cells (ECs) isolated from SIRT3 knockout (KO) mice, we revealed that the angiogenic capabilities were significantly reduced in SIRT3 deficient ECs. SIRT3 KO mice presented a pre-existing coronary microvascular dysfunction and microvascular rarefaction, as evidenced by a reduction in hyperemic peak diastolic blood flow velocity and coronary flow reserve (CFR), accompanied by loss of capillary-pericytes in the heart. Furthermore, SIRT3 KO mice subjected to myocardial ischemia by the ligation of left anterior descending coronary artery (LAD) exhibited more severe cardiac dysfunction together with decreased pericyte/EC coverage than that of wild type (WT) mice. In contrast, overexpression of SIRT3 preserved cardiac function in post-MI mice. Immunoblot analysis further showed that the expression of angiopoietin-1 (Ang-1), vascular endothelial growth factor (VEGF) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) were significantly decreased in the SIRT3-deficient ischemic hearts than those of WT ischemic hearts. This was accompanied by higher levels of cleaved caspase-3 and apoptosis. CONCLUSION:Our results reveal a potential mechanism by which SIRT3 deletion exacerbates post-MI cardiac dysfunction and impairment of cardiac recovery involving microvascular rarefaction and pre-existing coronary microvascular dysfunction.

journal_name

Int J Cardiol

journal_title

International journal of cardiology

authors

He X,Zeng H,Chen JX

doi

10.1016/j.ijcard.2016.04.092

subject

Has Abstract

pub_date

2016-07-15 00:00:00

pages

349-57

eissn

0167-5273

issn

1874-1754

pii

S0167-5273(16)30781-1

journal_volume

215

pub_type

杂志文章

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Ablation of SIRT3 causes coronary microvascular dysfunction and impairs cardiac recovery post myocardial ischemia.