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

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.

Orexin-A Reverse Bone Mass Loss Induced by Chronic Intermittent Hypoxia Through OX1R-Nrf2/HIF-1α Pathway

“…45 When exposed to chronic intermittent for a short time or at a slight/moderate hypoxia level, CIH promotes bone formation through up-regulating HIF-1α and activating angiogenesis via HIF-1α/VEGF pathway. 46 Chronic intermittent hypoxia in our study was much more severe and the increasing level of HIF-1α might activate proinflammatory cytokines in turn 5 which could inhibit osteogenic differentiation. 47 Multiple studies report that OSA patients have lower levels of orexin-A in the plasma.…”

“…We speculated that nerve damage and bone injury caused by long-term CIH acted much more than the protective effect in bone formation caused by the increasing level of HIF-1α. When exposed to chronic intermittent hypoxia, the increased level of HIF-1α could activate proinflammatory cytokines in turn 5 which could inhibit osteogenic differentiation, 47 while exogenous orexin-A alleviated inflammatory response, enhanced angiogenesis and promoted osteogenesis through HIF-1α/VEGF pathway.…”

“… 4 HIF-1α transcriptional activity can be powerfully promoted by hypoxia, which may in turn activate inflammatory cytokines. 5 In addition, chronic intermittent hypoxia can elevate sympathetic activity. 6 Previous research on OSA mainly focused on respiratory, cardiovascular and neurodegenerative diseases, but bone metabolism of OSA has rarely been studied.…”

Hydrogen sulfide plays an important role by regulating endoplasmic reticulum stress in myocardial diseases

“…3 Hydrogen sulfide plays an important role by regulating endoplasmic reticulum stress in ischemic/hypoxic myocardial disease Chronic intermittent hypoxia (CIH) is the main characteristic of the obstructive sleep apnea and an important risk factor of Frontiers in Pharmacology frontiersin.org myocardial diseases (Zhu et al, 2020;Hu et al, 2021). CIH induces myocardial injury mainly by promoting oxidative stress and inflammation (Wang et al, 2021). In order to study the influence Frontiers et al, 2018).…”

Chronic intermittent hypoxia accelerates cardiac dysfunction and cardiac remodeling during cardiac pressure overload in mice and can be alleviated by PHD3 overexpression

“…Ang II or transverse aortic constriction (TAC) surgery-induced cardiac pressure overload in animals can lead to HF. Oxygen-derived radicals, especially superoxide anion, produced during CIH lead to HIF-1α upregulation and its long-term high expression in cardiac tissue ( 19 , 20 ). We therefore speculate that CIH exposure could accelerate cardiac pressure overload-induced HF and that HIF-1α may be a new therapeutic target.…”