Role of HSP90 in suppressing TLR4-mediated inflammation in ischemic postconditioning

Article type: Research Article

Authors: Zhang, Xin-Yue^a | Huang, Zheng^{a; 1} | Li, Qing-Jie^b | Zhong, Guo-Qiang^{a; c; d} | Meng, Jian-Jun^e | Wang, Dong-Xiao^a | Tu, Rong-Hui^{c; d; f; *} | Hong-Wen, ^{e; f; *}

Affiliations: [a] Department of Cardiology, First Affiliated Hospital, Guang Xi Medical University, Nanning, China | [b] Department of Cardiology, Second Affiliated Hospital, Guang Xi Medical University, Nanning, China | [c] Guang Xi Key Laboratory of Precision Medicine in Cardio-cerebrovascular Disease Control and Prevention, Nanning, China | [d] Guang Xi Clinical Research Center for Cardio-cerebrovascular Diseases, Nanning, China | [e] Geriatric Healthcare Center, First Affiliated Hospital, Guang Xi Medical University, Nanning, China | [f] Department of Geriatric Cardiology, First Affiliated Hospital, Guang Xi Medical University, Nanning, China

Correspondence: [*] Corresponding authors: Rong-Hui Tu and Hong-Wen, Department of Geriatric Cardiology, First Affiliated Hospital, Guang Xi Medical University, 22 Shuangyong Road, Nanning, 530021, China. Tel.: +86771 5356590, Fax: +86771 5356592. E-mails: lily072trh@sina.com (R-H.Tu); wenhong120@126.com (H-W).

Note: [1] Both authors contributed equally to this manuscript.

Abstract: BACKGROUND:Myocardial inflammation mediated by toll-like receptor 4 (TLR4) plays an active role in myocardial ischemia/reperfusion (I/R) injury. Studies show that heat shock protein 90 (HSP90) is involved in ischemic postconditioning (IPostC) cardioprotection. This study investigates the roles of TLR4 and HSP90 in IPostC. METHODS:Rats were subjected to 30 min ischemia, then 2 h reperfusion. IPostC was applied by three cycles of 30 s reperfusion, then 30 s reocclusion at reperfusion onset. Sixty rats were randomly divided into four groups: sham, I/R, IPostC, and geldanamycin (GA, HSP90 inhibitor, 1 mg/kg) plus IPostC (IPostC + GA). RESULTS:IPostC significantly reduced I/R-induced infarct size (40.2±2.1% versus 28.4±2.4%; P < 0.05); the release of cardiac Troponin T, creatine kinase-MB, and lactate dehydrogenase (191.5±3.1 versus 140.6±3.3 pg/ml, 3394.6±132.7 versus 2880.7±125.5 pg/ml, 2686.2±98.6 versus 1848.8±90.1 pg/ml, respectively; P < 0.05); and cardiomyocyte apoptosis (40.3±2.2% versus 27.0±1.6%; P < 0.05). Further, local and circulating IL-1β, IL-6, TNF-α, and ICAM-1 levels decreased; TLR4 expression and nuclear factor-KB (NF-κB) signaling decreased; and cardiac HSP90 expression increased. Blocking HSP90 function with GA inhibited IPostC protection and anti-inflammation, suggesting that IPostC has a HSP90-dependent anti-inflammatory effect. CONCLUSION:HSP90 may play a role in IPostC-mediated cardioprotection by inhibiting TLR4 activation, local and systemic inflammation, and NF-kB signaling.

Keywords: Heat shock protein 90, ischemic postconditioning, toll-like receptor 4, nuclear factor-KB, inflammation

DOI: 10.3233/CH-200840

Journal: Clinical Hemorheology and Microcirculation, vol. 76, no. 1, pp. 51-62, 2020