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Published on: July 14, 2023
SRC-3 Knockout Attenuates Myocardial Injury Induced by Chronic Intermittent Hypoxia in Mice
Wanyu Wang1, Hongbo Gu2, Weihua Li3
1Department of Pulmonary and Critical Care Medicine of the First Affiliated Hospital of XiaMen University, The Third Clinical Medical College of Fujian Medical University, Teaching Hospital of Fujian Medical University, Xiamen, China.
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.
Insights
Chronic intermittent hypoxia (CIH), a model for sleep apnea syndrome, causes cardiac damage. Knocking out SRC-3 protein significantly reduces this CIH-induced heart injury by mitigating oxidative stress and inflammation.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Sleep Medicine
Background:
- Sleep apnea syndrome (SAS) is linked to cardiovascular complications.
- Chronic intermittent hypoxia (CIH) is a key pathological feature of SAS.
- The role of SRC-3 in CIH-induced cardiac dysfunction requires elucidation.
Purpose of the Study:
- To investigate the impact of CIH on cardiac function in mice.
- To determine the role of SRC-3 in the development of CIH-induced myocardial injury.
- To explore the molecular mechanisms underlying SRC-3's involvement in cardiac damage.
Main Methods:
- Utilized a mouse model of chronic intermittent hypoxia (CIH) for 12 weeks.
- Employed qRT-PCR, enzymatic assays, immunohistochemistry (IHC), transmission electron microscopy (TEM), and TUNEL staining.
- Compared wild-type mice with SRC-3 knockout (SRC3-KO) mice under normoxic and CIH conditions.
Main Results:
- CIH induced cardiac damage, evidenced by increased heart-to-body weight ratio, elevated oxidative stress markers (MDA, NOS, NO), inflammation (NF-κB), and apoptosis.
- SRC-3 knockout (SRC3-KO) mice exhibited ameliorated cardiac damage, reduced oxidative stress and inflammation, and decreased apoptosis compared to CIH wild-type mice.
- CIH upregulated specific genes (e.g., 11HSD2, COX-2, NOX2, HIF-1α, IL-1β, IL-6, iNOS, TNF-α, PC-1, TGF-β), with SRC-3 KO partially attenuating these changes.
Conclusions:
- CIH significantly contributes to cardiac damage via oxidative stress and inflammation.
- SRC-3 plays a critical role in mediating CIH-induced myocardial injury.
- Targeting SRC-3 may offer a therapeutic strategy to protect against cardiac dysfunction in sleep apnea syndrome.
