Role of cyclophilin A in aggravation of myocardial ischemia reperfusion injury via regulation of apoptosis mediated by thioredoxin-interacting protein

Article type: Research Article

Authors: Mahesutihan, Madina^a | Yan, Ju^a | Midilibieke, Hasidaer^a | Yu, Li^a | Dawulin, Reyizha^a | Yang, Wen-Xian^{b; *} | Wulasihan, Muhuyati^{a; c; *}

Affiliations: [a] Department of Integrated Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China | [b] CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China | [c] Xinjiang Medical University, Urumqi, China

Correspondence: [*] Corresponding authors. Wen-Xian Yang, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences No. 3, Yard 1, Beichen West Road, Chaoyang District, Beijing, 100101, China. E-mail: yangwenxian_ywx@126.com and Muhuyati Wulasihan, Department of Integrated Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, No. 567 of North Shangde Road, Urumqi, 830017, China. Tel.: 0991-436 6445; E-mail: Muhuyati0206@126.com.

Abstract: BACKGROUND: The progression and persistence of myocardial ischemia/reperfusion injury (MI/RI) are strongly linked to local inflammatory responses and oxidative stress. Cyclophilin A (CypA), a pro-inflammatory factor, is involved in various cardiovascular diseases. However, the role and mechanism of action of CypA in MI/RI are still not fully understood. METHODS: We used the Gene Expression Omnibus (GEO) database for bioinformatic analysis. We collected blood samples from patients and controls for detecting the levels of serum CypA using enzyme-linked immunosorbent assay (ELISA) kits. We then developed a myocardial ischemia/reperfusion (I/R) injury model in wild-type (WT) mice and Ppia-/- mice. We utilized echocardiography, hemodynamic measurements, hematoxylin and eosin (H&E) staining, immunohistochemistry, enzyme-linked immunosorbent assay, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining to determine the role of CypA in myocardial I/R injury. Finally, we conducted an in vitrostudy, cell transfection, flow cytometry, RNA interference, and a co-immunoprecipitation assay to clarify the mechanism of CypA in aggravating cardiomyocyte apoptosis. RESULTS: We found that CypA inhibited TXNIP degradation to enhance oxidative stress-induced cardiomyocyte apoptosis during MI/RI. By comparing and analyzing CypA expression in patients with coronary atherosclerotic heart disease and in healthy controls, we found that CypA was upregulated in patients with Coronary Atmospheric Heart Disease, and its expression was positively correlated with Gensini scores. In addition, CypA deficiency decreased cytokine expression, oxidative stress, and cardiomyocyte apoptosis in I/R-treated mice, eventually alleviating cardiac dysfunction. CypA knockdown also reduced H2O2-induced apoptosis in H9c2 cells. Mechanistically, we found that CypA inhibited K48-linked ubiquitination mediated by atrophin-interacting protein 4 (AIP4) and proteasomal degradation of TXNIP, a thioredoxin-binding protein that mediates oxidative stress and induces apoptosis. CONCLUSION: These findings highlight the critical role CypA plays in myocardial injury caused by oxidative stress-induced apoptosis, indicating that CypA can be a viable biomarker and a therapeutic target candidate for MI/RI.

Keywords: Cyclophilin A, inflammation, myocardial ischemia/reperfusion injury, oxidative stress, thioredoxin-interacting proteins

DOI: 10.3233/CH-242142

Journal: Clinical Hemorheology and Microcirculation, vol. 87, no. 4, pp. 491-513, 2024