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Angiotensin II induces apoptosis of cardiac microvascular endothelial cells via regulating PTP1B/PI3K/Akt pathway

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Abstract

Endothelial cell apoptosis and renin-angiotensin-aldosterone system (RAAS) activation are the major pathological mechanisms for cardiovascular disease and heart failure; however, the interaction and mechanism between them remain unclear. Investigating the role of PTP1B in angiotensin II (Ang II)–induced apoptosis of primary cardiac microvascular endothelial cells (CMECs) may provide direct evidence of the link between endothelial cell apoptosis and RAAS. Isolated rat CMECs were treated with different concentrations of Ang II to induce apoptosis, and an Ang II concentration of 4 nM was selected as the effective dose for the subsequent studies. The CMECs were cultured for 48 h with or without Ang II (4 nM) in the absence or presence of the PTP1B inhibitor TCS 401 (8 μM) and the PI3K inhibitor LY294002 (10 μM). The level of CMEC apoptosis was assessed by TUNEL staining and caspase-3 activity. The protein expressions of PTP1B, PI3K, Akt, p-Akt, Bcl-2, Bax, caspase-3, and cleaved caspase-3 were determined by Western blot (WB). The results showed that Ang II increased apoptosis of CMECs, upregulated PTP1B expression, and inhibited the PI3K/Akt pathway. Furthermore, cotreatment with PTP1B inhibitor significantly decreased the number of apoptotic CMECs induced by Ang II, along with increased PI3K expression, phosphorylation of Akt and the ratio of Bcl-2/Bax, decreased caspase-3 activity, and a cleaved caspase-3/caspase-3 ratio, while treatment with LY294002 partly inhibited the anti-apoptotic effect of the PTP1B inhibitor. Ang II induces apoptosis of primary rat CMECs via regulating the PTP1B/PI3K/Akt pathway.

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Funding

This study was supported by grants from the Program for the Outstanding Academic Leaders supported by Shanghai Science and Technology Commission (16XD1400700), National Basic Research Program of China (973 Program, 2012CB518605), National Natural Science Foundation of China (81370199) and Shanghai Sailing Program (19YF1406300).

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  1. Yanyan Wang and Yuyuan Fan contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Yanyan Wang, Yuyuan Fan, Yu Song, Xueting Han, Mingqiang Fu, Jingfeng Wang, Xiaotong Cui, Kai Hu, Aijun Sun, Jingmin Zhou & Junbo Ge

  2. North Sichuan Medical College, Nanchong, 637000, Sichuan, China

    Yuyuan Fan, Juan Cao & Li Chen

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  1. Yanyan Wang
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All applicable international and national guidelines for the care and use of animals were followed. The experiments with animals were approved by the ethical committees of the Zhongshan Hospital Affiliated to Fudan University.

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Wang, Y., Fan, Y., Song, Y. et al. Angiotensin II induces apoptosis of cardiac microvascular endothelial cells via regulating PTP1B/PI3K/Akt pathway. In Vitro Cell.Dev.Biol.-Animal 55, 801–811 (2019). https://doi.org/10.1007/s11626-019-00395-8

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