SGLT2 inhibitor dapagliflozin reduces endothelial dysfunction and microvascular damage during cardiac ischemia/reperfusion injury through normalizing the XO-SERCA2-CaMKII-coffilin pathways.
SGLT2 inhibitor dapagliflozin reduces endothelial dysfunction and microvascular damage during cardiac ischemia/reperfusion injury through normalizing the XO-SERCA2-CaMKII-coffilin pathways.
复制标题
SGLT 2抑制剂达格列净通过使XO-SERCA 2-CaMK II-coffilin通路正常化，减少心脏缺血/再灌注损伤期间的内皮功能障碍和微血管损伤。
DOI：
10.7150/thno.75121
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Wu, Yueheng
中科院分区：
文献类型：
--
作者：
Ma, Li;Zou, Rongjun;Shi, Wanting;Zhou, Na;Chen, Shaoxian;Zhou, Hao;Chen, Xinxin;Wu, Yueheng
背景：鉴于微血管损伤在梗死形成和扩张中的重要性，研究微血管保护心肌缺血/再灌注损伤（IRI）的治疗策略具有重要意义。在这里，我们探讨了SGLT2抑制剂dapagliflozin （DAPA）对IRI介导的心脏微血管功能障碍的保护作用的分子机制。方法：在体内（IRI小鼠）和体外(缺氧/再氧化（H/R）暴露的人冠状动脉内皮细胞（HCAECs）中评估DAPA的作用。DAPA预处理减轻了iri处理小鼠的管腔狭窄、内皮细胞肿胀和心脏微血管炎症。结果：在H/ r刺激的hcaec中，DAPA处理可改善内皮屏障功能、内皮一氧化氮合酶（eNOS）活性和血管生成能力，并通过阻止cofilin依赖性F-actin解聚和细胞骨架降解来抑制H/ r诱导的细胞凋亡。在dapa处理的hcaec中，进一步观察到H/ r诱导的黄嘌呤氧化酶（XO）激活和上调、sarco（内do）质网钙- atp酶2 （SERCA2）氧化和失活以及细胞质钙超载的抑制。DAPA还抑制了钙/钙调素（CaM）依赖性激酶II （CaMKII）的激活和cofilin的磷酸化，并在H/R后保持了细胞骨架的完整性和内皮细胞的活力。重要的是，在iri处理的serca2敲除小鼠中，DAPA对心脏微血管完整性和内皮细胞存活的有益作用在很大程度上被阻止。结论：这些结果表明，DAPA通过抑制XO-SERCA2-CaMKII-cofilin通路，有效减轻IRI期间的心脏微血管损伤和内皮功能障碍。
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.
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影响因子：
37.8
作者：
Goodman JB;Qin F;Morgan RJ;Chambers JM;Croteau D;Siwik DA;Hobai I;Panagia M;Luptak I;Bachschmid M;Tong X;Pimentel DR;Cohen RA;Colucci WS
通讯作者：
Colucci WS
影响因子：
7.4
作者：
Evangelista, Alicia M.;Thompson, Melissa D.;Bolotina, Victoria M.;Tong, XiaoYong;Cohen, Richard A.
通讯作者：
Cohen, Richard A.
影响因子：
9.3
作者：
Adingupu, Damilola D.;Gopel, Sven O.;Jonsson-Rylander, Ann-Cathrine
通讯作者：
Jonsson-Rylander, Ann-Cathrine
影响因子：
7.2
作者：
Bhattacharyya, Moitrayee;Karandur, Deepti;Kuriyan, John
通讯作者：
Kuriyan, John
影响因子：
7.4
作者：
Cook, Naomi L.;Viola, Helena M.;Davies, Michael J.
通讯作者：
Davies, Michael J.