NAD + administration decreases microvascular damage following cardiac ischemia/reperfusion by restoring autophagic flux
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ORIGINAL CONTRIBUTION
NAD+ administration decreases microvascular damage following cardiac ischemia/reperfusion by restoring autophagic flux You‑Jun Zhang1,2 · Mingchao Zhang3 · Xiaona Zhao1,2 · Kailei Shi1,2 · Maoqing Ye1,2 · Jiawen Tian1,2 · Shaofeng Guan1,2 · Weihai Ying3 · Xinkai Qu1,2 Received: 13 February 2020 / Accepted: 27 July 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Microvascular damage is a key pathological change in myocardial ischemia/reperfusion (I/R) injury. Using a rat model of myocardial I/R, our current study has provided the first evidence that nicotinamide adenine dinucleotide ( NAD+) administration can significantly attenuate myocardial I/R-induced microvascular damage, including reduced regional blood perfusion, decreased microvessel density and integrity, and coronary microvascular endothelial cells (CMECs) injury. In studies with primary cultured CMECs under hypoxia/reoxygenation (HR) and a rat model of I/R, our results suggested that the protective effect of N AD+ on CMECs exposed to HR or I/R is at least partially mediated by the N AD+-induced restoration of autophagic + flux, especially lysosomal autophagy: NAD treatment markedly induced transcription factor EB (TFEB) activation and attenuated lysosomal dysfunction in the I/R or HR-exposed cells. Collectively, our study has provided the first in vivo and in vitro evidence that NAD+ significantly rescued the impaired autophagic flux and cell apoptosis that was induced by I/R in rat CMECs, which is mediated in part through the action of TFEB-mediated lysosomal autophagy. Keywords NAD+ · Myocardial ischemia · Autophagic flux · Microvascular damage · Lysosomes
Introduction Despite prompt restoration of epicardial coronary flow after myocardial infarction, normalization of flow at the myocardial or microcirculatory level is not always assured. Estimates of the percent of patients who achieve normal epicardial flow but have some sign of suboptimal microcirculatory perfusion, which has been widely considered an independent risk factor for worse clinical outcomes, is up to 56.9% [6]. Thus, the reduction of microvascular damage is an important target for adjunctive treatment in addition to reperfusion [17, * Weihai Ying [email protected] * Xinkai Qu [email protected] 1
Department of Cardiology, Huadong Hospital, Fudan University, 221 West Yanan Road, Shanghai 200040, China
2
Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai 200040, China
3
Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China
18]. However, many approaches fail to be effective when translated into clinical research [16, 17]. Therefore, strategies to reduce coronary microvascular damage and final infarct size need to be further developed. Mechanisms underlying microvascular damage are multiple and interacting during myocardial ischemia/reperfusion (I/R), including coronary microvascular endothelial cells (CMECs) swelling, alterat
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