| As our country gradually enters the ranks of aging countries,thehe prevalence of cardiovascular diseases in China is increasing year by year,and cardiovascular disease still ranks first in the mortality rate.Atherosclerosis(AS)is the most common arterial vascular disease,a chronic inflammatory disease of lipid metabolism disorder and abnormal immune response.The accumulation of cholesterolrich macrophages in the blood vessel wall,the proliferation of vascular smooth muscle cells,the increase of collagen fibers,and the formation of atherosclerotic lipidcontaining necrosis and vascular wall sclerosis are the characteristics of pathological changes.Coronary arteries are blood vessels that supply blood and oxygen to myocardial cells.When atherosclerosis,thromboembolism,or vascular spasm occurs,the lumen will be narrowed or even blocked,and blood flow will be blocked,so that the downstream myocardium will not get sufficient blood perfusion.This leads to the appearance of myocardial ischemia.Myocardial ischemia occurs.Reperfusion of the ischemic heart can restore cardiac function.Reperfusion therapy improves myocardial blood supply and is accompanied by a series of pathophysiological processes,including peroxidation,inflammation,intracellular calcium overload,and finally irreversible cell apoptosis.Death and necrosis.This myocardial injury caused by reperfusion injury is called reperfusion injury(Myocardial ischemia-reperfusion injury,MI/RI).Inflammatory reactions occur during the occurrence of cardiovascular diseases.Under normal circumstances,the body needs to precisely regulate the inflammatory response.Excessive inflammation will cause more serious damage to the body.Macrophages are the main participants in the pathogenesis of many chronic inflammation and autoimmune diseases,such as atherosclerosis,myocardial infarction and myocardial ischemia-reperfusion injury and.In these diseases,M1 macrophages are an important source of many inflammatory cytokines.Inducible Nitric oxide synthase(iNOS)is mainly produced by macrophages,and the inflammatory response mediated by it is involved in the pathological process of AS and MIRI.The transcriptional regulation of iNOS mainly relies on the NF-κB signaling pathway,although the epigenetic mechanism is not fully understood.Epigenetic regulation is different from gene recombination and mutation.It has reversibility and dynamic plasticity and is suitable for therapeutic operations,which provides an optimistic prospect for disease prevention and treatment.It is expected to provide new potential targets for the treatment of cardiovascular diseases when the epigenetic regulation mechanism of iNOS is clearly understood.Myocardin-related transcription factor A(MRTF-A)is an important regulator of cardiovascular disease.Different laboratories have found that MRTF-A can promote myocardial infarction,myocardial hypertrophy,and AS.Early in our laboratory,MRTFA has been shown to participate in vascular remodeling,hypoxic pulmonary hypertension,and ischemia-reperfusion injury.MRTF-A can interact with other sequence-specific transcription factors(TF),such as NF-κB,Sp1 and Smad3.One important feature of MRTF-A is that it can tie the epigenetic machinery to regulate these TF-mediated transcription events.The epigenetic mechanism whereby MRTF-A activates the transcription of iNOS genes that depend on NF-κB is unclear.We found that macrophages specifically deletion of MRTF-A,or giving CCG-1423 to inhibit MRTF-A activity can all mitigate iNOS expression.Under the conditions of lipopolysaccharide(LPS)stimulation to simulate the inflammatory environment of atherosclerosis,and Hypoxia/Reoxygenation(H/R)stimulation to simulate MIRI,silencing or inhibiting MRTF-A can significantly alleviate iNOS transcription.In addition,we observed that when MRTF-A silencing or CCG-1423 treatment in the macrophages,the histone modifications surrounding the iNOS promoter were incresed,including histone H3K4 methylation and H3,H4 acetylation,which were consistent with its transcriptional activation.Further analysis revealed that MRTF-A interacted with H3K4 methyltransferase ASH2 or H4K16 acetyltransferase TIP60 to synergistically activate iNOS transcription.Similarly,the silencing of ASH2 or Tip60 will also down-regulate the transcription of iNOS.In addition,ASH2 and Tip60 may have a crosstalk to regulate iNOS transcription.In conclusion,our data suggest that MRTF-A may simultaneously recruit different histone-modifying enzymes to regulate the transcriptional activation of the pro-inflammatory factor iNOS in macrophages.These results provide new and effective evidence for targeting MRTFA to interfere with atherosclerosis and cardiac ischemia/reperfusion injury... |
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