SRC-3 Knockout Attenuates Myocardial Injury Induced by Chronic Intermittent Hypoxia in Mice.

Wanyu Wang,Shenhui Huang,Fang Lu,Zhengrong Huang,Yonghong Shi,Wen Luo,Yihua Lin,Hongbo Gu,Xiangyang Yao,Weihua Li,Dragan Hrnčić

doi:10.1155/2021/6372430

Abstract

This study investigated the effects of chronic intermittent hypoxia (CIH), a model of sleep apnea syndrome (SAS), on cardiac function. SRC-3 was extremely lowly expressed in the adult mouse heart tissue, while SRC-3 was highly expressed in the adult mouse heart tissue after CIH, suggesting that SRC-3 is involved in CIH model. We further studied the role of SRC-3 in CIH-induced myocardial injury in mice. Twenty-four healthy Balb/c male mice (n = 16, wild type; n = 8, SRC-3 knockout (SRC3-KO)) were randomly divided into three groups: air control (Ctrl), CIH, and CIH+SRC3-KO. Mice were exposed to CIH for 12 weeks. qRT-PCR was used to evaluate cardiac expression of the following genes: 11HSD1, 11HSD2, GR, MR, COX-2, OPN, NOX2, HIF-1-α, IL-1β, IL-6, iNOS, TNF-α, PC-1, and TGF-β. Enzymatic levels of SOD, CAT, MDA, NOS, and NO in the mouse hearts were determined using commercially available kits. Immunohistochemistry (IHC) was used to evaluate NF-κB expression in cardiac tissues. A transmission electron microscope (TEM) was used to evaluate myocardial ultrastructure. TUNEL staining was used to assess myocardial cell apoptosis. CIH induced cardiac damage, which was ameliorated in the SRC-3 KO mice. CIH significantly increased the heart-to-body weight ratio, expression of all aforementioned genes except 11HSD1, GR, and MR, and increased the levels of MDA, NOS, NO, and NF-κB, which were attenuated in the SRC-3 KO mice. The CIH group had the lowest SOD and CAT levels, which were partially recovered in the CIH+SRC3-KO group. 11HSD2 gene expression was elevated in both the CIH and CIH+SRC3-KO groups compared to the Ctrl group. The CIH group had severe myocardial cell apoptosis and mitochondrial dysfunction, which were alleviated in the CIH+SRC3-KO group. CIH causes cardiac damage through inducing oxidative stress and inflammation. Knockout of SRC-3 ameliorates CIH-induced cardiac damage through antagonizing CIH-triggered molecular changes in cardiac tissue.

Highlights

Sleep apnea syndrome (SAS) is prevalent in the general population and associated with cardiovascular diseases (CVDs) [1]
To examine the role of Steroid receptor coactivator-3 (SRC-3) in CIHinduced cardiac hypertrophy, we first determined if Chronic intermittent hypoxia (CIH) altered the expression of SRC-3 in mouse hearts
CIH induced cardiac hypertrophy as evaluated by the heart weight/body weight ratio (Figure 1(b), ∗∗∗∗p < 0:0001 vs. Ctrl), which was significantly attenuated in the SRC-3 KO mice (Figure 1(b), ∗p < 0:05 vs. CIH)

Summary

Introduction

Sleep apnea syndrome (SAS) is prevalent in the general population and associated with cardiovascular diseases (CVDs) [1]. Reactive oxygen species (ROS) induced by CIH activate hypoxia inducible fator-1α (HIF-1α), which in turn promotes sustained oxidative stress, further exacerbating myocardial inflammation [6] and Oxidative Medicine and Cellular Longevity resulting in myocardial damage, atherosclerosis, and hypertension. CIH was shown to increase vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) expression through HIF-1α, a pathophysiological process that may play an important role in the pathogenesis of SAS and cardiovascular damage [7]. Given that ROS, HIF-1α, and nuclear factor-κB (NF-κB) play a pivotal role in CIH-induced myocardial injury [6,7,8], it is critical to attenuate oxidative stress and inflammation to protect against CIH-induced myocardial injury

Methods

Results

Discussion

Conclusion