Exercise improves cardiac function and attenuates myocardial inflammation and apoptosis by regulating APJ/STAT3 in mice with stroke

Li Wang; Wenzhan Tu; Xuqing Li; Caiyan Li; Junhong Lu; Peng Dai; Yuewei Chen; Meilin Gu; Ming Li; Songhe Jiang; Guanhu Yang; Shengcun Li

doi:10.1016/j.lfs.2023.122041

Exercise improves cardiac function and attenuates myocardial inflammation and apoptosis by regulating APJ/STAT3 in mice with stroke

Life Sci. 2023 Nov 1:332:122041. doi: 10.1016/j.lfs.2023.122041. Epub 2023 Aug 30.

Authors

Li Wang¹, Wenzhan Tu², Xuqing Li², Caiyan Li³, Junhong Lu², Peng Dai³, Yuewei Chen², Meilin Gu², Ming Li⁴, Songhe Jiang⁴, Guanhu Yang⁵, Shengcun Li⁶

Affiliations

¹ Rehabilitation Medicine Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
² Rehabilitation Medicine Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China.
³ Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
⁴ Rehabilitation Medicine Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China; The Wenzhou Key Laboratory for Rehabilitation Research, The Provincial Key Laboratory for Acupuncture and Rehabilitation in Zhejiang Province, Wenzhou 325027, Zhejiang, China.
⁵ Rehabilitation Medicine Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China; The Wenzhou Key Laboratory for Rehabilitation Research, The Provincial Key Laboratory for Acupuncture and Rehabilitation in Zhejiang Province, Wenzhou 325027, Zhejiang, China; Department of Specialty Medicine, Ohio University, Athens, OH 45701, United States.
⁶ Rehabilitation Medicine Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China; The Wenzhou Key Laboratory for Rehabilitation Research, The Provincial Key Laboratory for Acupuncture and Rehabilitation in Zhejiang Province, Wenzhou 325027, Zhejiang, China. Electronic address: lishengcun@wmu.edu.cn.

PMID: 37657526
DOI: 10.1016/j.lfs.2023.122041

Abstract

Stroke can induce cardiac dysfunction without a primary cardiac disease. Exercise can promote the overall rehabilitation of stroke patients and be beneficial for all kinds of heart diseases. However, the mechanisms underlying the protective effects of exercise in stroke-induced cardiac dysfunction are poorly understood. Hence, we aimed to distinguish the different effects of acute and long-term exercise and further study the mechanism of protection against cardiomyopathy caused by stroke. Mice underwent a single acute session or long-term exercise for 30 days, followed by middle cerebral artery occlusion surgery. The expression of apoptosis-related proteins and proinflammatory factors in the heart was evaluated. Then, overexpression of apelin peptide jejunum (APJ) transfected adeno-associated virus type 9 (AAV9) and inhibition of signal transducer and activator of transcription 3 (STAT3) by Stattic were used in stroke mice or hypoxic cardiomyocytes. ML221 were used to inhibit APJ activity in exercise mouse. Thereafter, changes in apoptotic and proinflammatory factors were evaluated. The results demonstrated that chronic exercise prevented myocardial inflammation, apoptosis and cardiac dysfunction after stroke. However, acute exercise did not have similar effects. Exercise maintained the levels of APJ expression and decreased phosphorylated-STAT3 (p-STAT3) activation to protect cardiomyocytes. Moreover, APJ overexpression promoted cardiomyocyte survival and reduced p-STAT3 levels. STAT3 inhibition also reduced apoptosis and proinflammatory factors in mice hearts. Conversely, the protective effect of exercise was eliminated by APJ inhibition. This study showed that exercise can maintain APJ expression and inhibit p-STAT3, thus, conferring protection against myocardial inflammation and apoptosis induced by stroke.

Keywords: APJ; Cardiac dysfunction; Exercise; Ischemic stroke; STAT3.