Myeloid differentiation protein 1 protected myocardial function against high‐fat stimulation induced pathological remodelling

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.

The Crosstalk between Cardiac Lipotoxicity and Mitochondrial Oxidative Stress in the Cardiac Alterations in Diet-Induced Obesity in Rats

“…MitoQ ameliorated the increase in CPT1A, CycloF, and Cyto C induced by PA in these cells, in agreement with our in vivo data. It has consistently been reported that PA interferes with several signaling pathways, including the Erk and NF-κB pathways [58,59]. Therefore, these data suggest interactions between lipotoxicity and mitochondrial oxidative stress, which regulate downstream events responsible for cardiac alterations in the context of obesity.…”

The effect of MD1 on potassium and L-type calcium current of cardiomyocytes from high-fat diet mice

“…Obesity-related cardiac remodeling is the important pathological manifestation of sudden cardiac death (SCD) [15]. In earlier work, our group found that HFD could induce pathological cardiac remodeling and increase susceptibility to VA [9]. Moreover, excessive APD prolongation is a hallmark of the abnormally altered electrophysiology or adverse electrical remodeling [16,17].…”

“…Our previous studies found that MD1 expression was downregulated in heart failure patients [6,7], and loss of MD1 could worsen structural and electrical remodeling under pressure overload and ischemia/reperfusion injury conditions via increased the activation of the TLR4 signaling pathway [6,8]. Interestingly, we also found that MD1 deletion had no significant effect on the cardiac structure in wild-type (WT) mice under physiological conditions [6][7][8][9][10][11]. Moreover, downregulated MD1 does not activate the TLR4 signaling pathway in both in vitro and in vivo experiments [7,9].…”

“…Interestingly, we also found that MD1 deletion had no significant effect on the cardiac structure in wild-type (WT) mice under physiological conditions [ 6 – 11 ]. Moreover, downregulated MD1 does not activate the TLR4 signaling pathway in both in vitro and in vivo experiments [ 7 , 9 ]. Our current study also observed that MD1 is downregulated in the obese mouse heart, and MD1 protected cardiac function against high-fat diet (HFD)-induced pathological remodeling [ 9 , 11 ].…”

“…Moreover, downregulated MD1 does not activate the TLR4 signaling pathway in both in vitro and in vivo experiments [ 7 , 9 ]. Our current study also observed that MD1 is downregulated in the obese mouse heart, and MD1 protected cardiac function against high-fat diet (HFD)-induced pathological remodeling [ 9 , 11 ]. Furthermore, MD1 deletion could also significantly prolong action potential duration (APD) and increase susceptibility to VA through enhanced activation of the TLR4/MyD88/CaMKII signaling pathway in the ex vivo Langendorff-perfused hearts of HFD-induced obese mice [ 10 ].…”