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Theranostics 2022; 12(11):5034-5050. doi:10.7150/thno.75121 This issue Cite

Research Paper

SGLT2 inhibitor dapagliflozin reduces endothelial dysfunction and microvascular damage during cardiac ischemia/reperfusion injury through normalizing the XO-SERCA2-CaMKII-coffilin pathways

Li Ma^1#, Rongjun Zou^1#, Wanting Shi², Na Zhou¹, Shaoxian Chen³, Hao Zhou^4✉, Xinxin Chen^1✉, Yueheng Wu^3✉

1. Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
2. Department of Paediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
3. Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.
4. Senior Department of Cardiology, The Sixth Medical Center of People's Liberation Army General Hospital, Beijing, China.
#These authors equally contributed to this article.

✉ Corresponding authors: Hao Zhou, E-mail: zhouhaoorg; Senior Department of Cardiology, The Sixth Medical Center of People's Liberation Army General Hospital, Beijing, China. Xinxin Chen, E-mail: xinxinchengzcom; Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. Yueheng Wu, E-mail: wuyuehengorg.cn; Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China. More

Abstract

Background: Given the importance of microvascular injury in infarct formation and expansion, development of therapeutic strategies for microvascular protection against myocardial ischemia/reperfusion injury (IRI) is of great interest. Here, we explored the molecular mechanisms underlying the protective effects of the SGLT2 inhibitor dapagliflozin (DAPA) against cardiac microvascular dysfunction mediated by IRI.

Methods: DAPA effects were evaluated both in vivo, in mice subjected to IRI, and in vitro, in human coronary artery endothelial cells (HCAECs) exposed to hypoxia/reoxygenation (H/R). DAPA pretreatment attenuated luminal stenosis, endothelial swelling, and inflammation in cardiac microvessels of IRI-treated mice.

Results: In H/R-challenged HCAECs, DAPA treatment improved endothelial barrier function, endothelial nitric oxide synthase (eNOS) activity, and angiogenic capacity, and inhibited H/R-induced apoptosis by preventing cofilin-dependent F-actin depolymerization and cytoskeletal degradation. Inhibition of H/R-induced xanthine oxidase (XO) activation and upregulation, sarco(endo)plasmic reticulum calcium-ATPase 2 (SERCA2) oxidation and inactivation, and cytoplasmic calcium overload was further observed in DAPA-treated HCAECs. DAPA also suppressed calcium/Calmodulin (CaM)-dependent kinase II (CaMKII) activation and cofilin phosphorylation, and preserved cytoskeleton integrity and endothelial cell viability following H/R. Importantly, the beneficial effects of DAPA on cardiac microvascular integrity and endothelial cell survival were largely prevented in IRI-treated SERCA2-knockout mice.

Conclusions: These results indicate that DAPA effectively reduces cardiac microvascular damage and endothelial dysfunction during IRI through inhibition of the XO-SERCA2-CaMKII-cofilin pathway.

Keywords: Dapagliflozin, microvascular dysfunction, cardiac ischemia/reperfusion injury, XO, SERCA2, CaMKII, cofilin

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