Role of GADD45A in myocardial ischemia/reperfusion through mediation of the JNK/p38 MAPK and STAT3/VEGF pathways

Wang,Yang; Gao,Hui; Cao,Xianghong; Li,Zheng; Kuang,Ye; Ji,Yong; Li,Yi

doi:10.3892/ijmm.2022.5200

Role of GADD45A in myocardial ischemia/reperfusion through mediation of the JNK/p38 MAPK and STAT3/VEGF pathways

Authors:
- Yang Wang
- Hui Gao
- Xianghong Cao
- Zheng Li
- Ye Kuang
- Yong Ji
- Yi Li
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Affiliations: Department of Clinical Laboratory, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650051, P.R. China
Published online on: November 3, 2022 https://doi.org/10.3892/ijmm.2022.5200
Article Number: 144
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Rapid recovery of blocked coronary artery blood flow after myocardial infarction (MI) is the key to reducing the size of the infarcted area, improving clinical outcome and decreasing mortality. However, ischemia/reperfusion (I/R) injury has a complicated pathological mechanism and is an inevitable complication of coronary artery blood flow recovery. Growth arrest and DNA damage‑inducible α (GADD45A) serves a vital role in myocardial injury induced by I/R. The present study aimed to explore the role and mechanisms of GADD45A in cardiac microvascular endothelial cells (CMEC)‑I/R injury in vivo and in vitro. An I/R injury rat model and a hypoxia/reoxygenation (H/R) cellular model were established, and myocardial tissues were collected for GADD45A detection, 2,3,5‑triphenyltetrazolium chloride staining, H&E staining, and dual staining of CD31 and TUNEL. Serum was also collected for the analysis of creatine kinase and lactate dehydrogenase in I/R rats following GADD45A silencing. Additionally, the protein expression levels of CD31, phosphorylated‑endothelial nitric oxide synthase (p‑eNOS), endothelin‑1 (ET‑1), JNK, p38 MAPK, STAT3 and VEGF were assessed by western blotting. The JNK and p38 MAPK activator, anisomycin, and the JAK2‑STAT3 pathway inhibitor, AG490, were used to determine the involvement of JNK/p38 MAPK pathway and STAT3/VEGF pathway. GADD45A was highly expressed in I/R injury rat and cell models. GADD45A silencing reduced the ischemic area and improved myocardial pathological damage in vivo. Furthermore, the levels of CD31 and p‑eNOS were increased, whereas ET‑1 was decreased by GADD45A silencing in the I/R injury rats. Mechanistically, GADD45A silencing reduced JNK/p38 MAPK expression but activated STAT3/VEGF expression. GADD45A silencing inhibited H/R‑induced viability reduction and apoptosis through MAPK signaling and suppressed angiogenesis via STAT3/VEGF in H/R‑induced CMECs. Overall, GADD45A ameliorated apoptosis and functional injury of CMECs via the JNK/p38 MAPK and STAT3/VEGF pathways.

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