2. Academic Validation
  3. Pinacidil ameliorates cardiac microvascular ischemia-reperfusion injury by inhibiting chaperone-mediated autophagy of calreticulin

Pinacidil ameliorates cardiac microvascular ischemia-reperfusion injury by inhibiting chaperone-mediated autophagy of calreticulin

  • Basic Res Cardiol. 2024 Jan 2. doi: 10.1007/s00395-023-01028-8.
Muyin Liu # 1 2 3,  Su Li # 1 2 3,  Ming Yin # 1 2 3,  Youran Li 1 2 3,  Jinxiang Chen 1 2 3,  Yuqiong Chen 4,  You Zhou 1 2 3,  Qiyu Li 1 2 3,  Fei Xu 5,  Chunfeng Dai 1,  Yan Xia 1 2 3,  Ao Chen 1 2 3,  Danbo Lu 1 2 3,  Zhangwei Chen 6 7 8,  Juying Qian 9 10 11,  Junbo Ge 12 13 14
Affiliations

Affiliations

  • 1 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • 2 Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China.
  • 3 National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China.
  • 4 Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, Nanjing, China.
  • 5 Department of Cardiology, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
  • 6 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. chen.zhangwei@zs-hospital.sh.cn.
  • 7 Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China. chen.zhangwei@zs-hospital.sh.cn.
  • 8 National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China. chen.zhangwei@zs-hospital.sh.cn.
  • 9 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. qian.juying@zs-hospital.sh.cn.
  • 10 Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China. qian.juying@zs-hospital.sh.cn.
  • 11 National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China. qian.juying@zs-hospital.sh.cn.
  • 12 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. jbge@zs-hospital.sh.cn.
  • 13 Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China. jbge@zs-hospital.sh.cn.
  • 14 National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China. jbge@zs-hospital.sh.cn.
  • # Contributed equally.
PMID: 38168863 DOI: 10.1007/s00395-023-01028-8
Abstract

Calcium overload is the key trigger in cardiac microvascular ischemia-reperfusion (I/R) injury, and calreticulin (CRT) is a calcium buffering protein located in the endoplasmic reticulum (ER). Additionally, the role of pinacidil, an antihypertensive drug, in protecting cardiac microcirculation against I/R injury has not been investigated. Hence, this study aimed to explore the benefits of pinacidil on cardiac microvascular I/R injury with a focus on endothelial calcium homeostasis and CRT signaling. Cardiac vascular perfusion and no-reflow area were assessed using FITC-lectin perfusion assay and Thioflavin-S staining. Endothelial calcium homeostasis, CRT-IP3Rs-MCU signaling expression, and Apoptosis were assessed by real-time calcium signal reporter GCaMP8, western blotting, and fluorescence staining. Drug affinity-responsive target stability (DARTS) assay was adopted to detect proteins that directly bind to pinacidil. The present study found pinacidil treatment improved capillary density and perfusion, reduced no-reflow and infraction areas, and improved cardiac function and hemodynamics after I/R injury. These benefits were attributed to the ability of pinacidil to alleviate calcium overload and mitochondria-dependent Apoptosis in cardiac microvascular endothelial cells (CMECs). Moreover, the DARTS assay showed that pinacidil directly binds to HSP90, through which it inhibits chaperone-mediated Autophagy (CMA) degradation of CRT. CRT overexpression inhibited IP3Rs and MCU expression, reduced mitochondrial calcium inflow and mitochondrial injury, and suppressed endothelial Apoptosis. Importantly, endothelial-specific overexpression of CRT shared similar benefits with pinacidil on cardiovascular protection against I/R injury. In conclusion, our data indicate that pinacidil attenuated microvascular I/R injury potentially through improving CRT degradation and endothelial calcium overload.

Keywords

Calcium overload; Calreticulin; Cardiac microvascular ischemia–reperfusion injury; Chaperone-mediated autophagy; Mitochondrial injury; Pinacidil.

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