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雌激素通过上调 SERCA2a 抑制内质网应激，改善大鼠心肌缺血/再灌注损伤。

Estrogen inhibits endoplasmic reticulum stress and ameliorates myocardial ischemia/reperfusion injury in rats by upregulating SERCA2a.

机构信息

Institute of Cardiovascular Disease Research, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, People's Republic of China.

Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, 221002, Jiangsu, People's Republic of China.

出版信息

Cell Commun Signal. 2022 Mar 24;20(1):38. doi: 10.1186/s12964-022-00842-2.

DOI:10.1186/s12964-022-00842-2
PMID:35331264
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8944077/
Abstract

BACKGROUND

The incidence of coronary heart disease (CHD) in premenopausal women is significantly lower than that of men of the same age, suggesting protective roles of estrogen for the cardiovascular system against CHD. This study aimed to confirm the protective effect of estrogen on myocardium during myocardial ischemia/reperfusion (MI/R) injury and explore the underlying mechanisms.

METHODS

Neonatal rat cardiomyocytes and Sprague-Dawley rats were used in this study. Different groups were treated by bilateral ovariectomy, 17β-estradiol (E2), adenoviral infection, or siRNA transfection. The expression of sarcoplasmic reticulum Ca ATPase pump (SERCA2a) and endoplasmic reticulum (ER) stress-related proteins were measured in each group to examine the effect of different E2 levels and determine the relationship between SERCA2a and ER stress. The cell apoptosis, myocardial infarction size, levels of apoptosis and serum cardiac troponin I, ejection fraction, calcium transient, and morphology changes of the myocardium and ER were examined to verify the effects of E2 on the myocardium.

RESULTS

Bilateral ovariectomy resulted in reduced SERCA2a levels and more severe MI/R injury. E2 treatment increased SERCA2a expression. Both E2 treatment and exogenous SERCA2a overexpression decreased levels of ER stress-related proteins and alleviated myocardial damage. In contrast, SERCA2a knockdown exacerbated ER stress and myocardial damage. Addition of E2 after SERCA2a knockdown did not effectively inhibit ER stress or reduce myocardial injury.

CONCLUSIONS

Our data demonstrate that estrogen inhibits ER stress and attenuates MI/R injury by upregulating SERCA2a. These results provide a new potential target for therapeutic intervention and drug discovery in CHD. Video Abstract.

摘要

背景

绝经前女性的冠心病（CHD）发病率明显低于同龄男性，这表明雌激素对心血管系统具有保护作用，可以预防 CHD。本研究旨在确认雌激素在心肌缺血/再灌注（MI/R）损伤期间对心肌的保护作用，并探讨其潜在机制。

方法

本研究使用新生大鼠心肌细胞和 Sprague-Dawley 大鼠。通过双侧卵巢切除术、17β-雌二醇（E2）、腺病毒感染或 siRNA 转染对不同组进行处理。测量各组肌浆网 Ca2+-ATP 酶泵（SERCA2a）和内质网（ER）应激相关蛋白的表达，以检查不同 E2 水平的影响，并确定 SERCA2a 与 ER 应激之间的关系。通过检查细胞凋亡、心肌梗死面积、凋亡水平和血清心肌肌钙蛋白 I、射血分数、钙瞬变以及心肌和 ER 的形态变化，验证 E2 对心肌的作用。

结果

双侧卵巢切除导致 SERCA2a 水平降低和更严重的 MI/R 损伤。E2 处理增加了 SERCA2a 的表达。E2 处理和外源性 SERCA2a 过表达均降低了 ER 应激相关蛋白的水平，并减轻了心肌损伤。相反，SERCA2a 敲低加剧了 ER 应激和心肌损伤。SERCA2a 敲低后添加 E2 并不能有效抑制 ER 应激或减轻心肌损伤。

结论

我们的数据表明，雌激素通过上调 SERCA2a 抑制 ER 应激并减轻 MI/R 损伤。这些结果为 CHD 的治疗干预和药物发现提供了一个新的潜在靶点。视频摘要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f68d/8944077/bd7d8d1a1c4c/12964_2022_842_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f68d/8944077/994965e848d6/12964_2022_842_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f68d/8944077/f23288e29c0c/12964_2022_842_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f68d/8944077/7b08036366dd/12964_2022_842_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f68d/8944077/2e8f04e46edf/12964_2022_842_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f68d/8944077/0123d2348fec/12964_2022_842_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f68d/8944077/bd7d8d1a1c4c/12964_2022_842_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f68d/8944077/994965e848d6/12964_2022_842_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f68d/8944077/f23288e29c0c/12964_2022_842_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f68d/8944077/7b08036366dd/12964_2022_842_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f68d/8944077/2e8f04e46edf/12964_2022_842_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f68d/8944077/0123d2348fec/12964_2022_842_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f68d/8944077/bd7d8d1a1c4c/12964_2022_842_Fig6_HTML.jpg

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