Abstract
Myeloid differentiation 1 (MD‐1) is a secreted protein that regulates the immune response of B cell through interacting with radioprotective 105 (RP105). Disrupted immune response may contribute to the development of cardiac diseases, while the roles of MD‐1 remain elusive. Our studies aimed to explore the functions and molecular mechanisms of MD‐1 in obesity‐induced cardiomyopathy. H9C2 myocardial cells were treated with free fatty acid (FFA) containing palmitic acid and oleic acid to challenge high‐fat stimulation and adenoviruses harbouring human MD‐1 coding sequences or shRNA for MD‐1 overexpression or knockdown in vitro. MD‐1 overexpression or knockdown transgenic mice were generated to assess the effects of MD‐1 on high‐fat diet (HD) induced cardiomyopathy in vivo. Our results showed that MD‐1 was down‐regulated in H9C2 cells exposed to FFA stimulation for 48 hours and in obesity mice induced by HD for 20 weeks. Both in vivo and in vitro, silencing of MD‐1 accelerated myocardial function injury induced by HD stimulation through increased cardiac hypertrophy and fibrosis, while overexpression of MD‐1 alleviated the effects of HD by inhibiting the process of cardiac remodelling. Moreover, the MAPK and NF‐κB pathways were overactivated in MD‐1 deficient mice and H9C2 cells after high‐fat treatment. Inhibition of MAPK and NF‐κB pathways played a cardioprotective role against the adverse effects of MD‐1 silencing on high‐fat stimulation induced pathological remodelling. In conclusion, MD‐1 protected myocardial function against high‐fat stimulation induced cardiac pathological remodelling through negative regulation for MAPK/NF‐κB signalling pathways, providing feasible strategies for obesity cardiomyopathy.
Highlights
Obesity is a metabolic disorder affecting millions of people world‐ wide
Wang et al reported that chronic high‐fat diet induced myocardial hypertrophy and fibrosis by inhibiting GSK‐3β and up‐regulating the transcription factors yes‐associated protein (YAP1) and nuclear GATA binding protein 4 (GATA4) in HD mice, which induced the transcription expres‐ sion of hypertrophy‐related genes.[28]
A recent study suggested that disrupted metabolism in early obesity interfering immune responses in cardiomyocytes, resulting in fibrosis and hypertro‐ phy.[27]
Summary
Obesity is a metabolic disorder affecting millions of people world‐ wide. Patients with obesity are highly vulnerable to cardiovascular dysfunctions, including hypertrophic cardiomyopathy.[1,2] Featured with impaired diastolic function and left ventricular hypertrophy, obesity cardiomyopathy (OCM) patients exhibited disrupted sub‐ strate metabolism, oxidative stress, endoplasmic reticulum stress in the early stage.[2-7]. Featured with impaired diastolic function and left ventricular hypertrophy, obesity cardiomyopathy (OCM) patients exhibited disrupted sub‐ strate metabolism, oxidative stress, endoplasmic reticulum stress in the early stage.[2-7]. These events cause the accumulation of lipid droplets in cardiomyocytes, changing the immune response and resulting in cardiac fibrosis, remodelling and compromised cardiac functions.[8-10]. Myeloid differentiation 1 (MD‐1) is a secreted glycoprotein produced by macrophages.[11] It forms complex with radioprotec‐ tive 105 (RP105), a Toll‐like receptor protein, to play critical roles in lipopolysaccharide (LPS) recognition by B cells.[11-13]. Another study found that MD1 deficiency played an important role in accelerating the development of inflammatory atrial fibrosis and increasing vul‐ nerability to AF in mice with HFD‐fed induced obesity.[20]. Our studies are beneficial to better understand the mechanisms of obesity cardiomyopathy and provided a new strategy to treat obesity cardiomyopathy through targeting MD‐1
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