ABSTRACT
Vascular smooth muscle cell (SMC) from arterial stenotic-occlusive diseases is featured with deficiency in mitochondrial respiration and loss of cell contractility. However, the regulatory mechanism of mitochondrial genes and mitochondrial energy metabolism in SMC remains elusive. Here, we described that DNA methyltransferase 1 (DNMT1) translocated to the mitochondria and catalyzed D-loop methylation of mitochondrial DNA in vascular SMCs in response to platelet-derived growth factor-BB (PDGF-BB). Mitochondrial-specific expression of DNMT1 repressed mitochondrial gene expression, caused functional damage, and reduced SMC contractility. Hypermethylation of mitochondrial D-loop regions were detected in the intima-media layer of mouse carotid arteries subjected to either cessation of blood flow or mechanical endothelial injury, and also in vessel specimens from patients with carotid occlusive diseases. Likewise, the ligated mouse arteries exhibited an enhanced mitochondrial binding of DNMT1, repressed mitochondrial gene expression, defects in mitochondrial respiration, and impaired contractility. The impaired contractility of a ligated vessel could be restored by ex vivo transplantation of DNMT1-deleted mitochondria. In summary, we discovered the function of DNMT1-mediated mitochondrial D-loop methylation in the regulation of mitochondrial gene transcription. Methylation of mitochondrial D-loop in vascular SMCs contributes to impaired mitochondrial function and loss of contractile phenotype in vascular occlusive disease.
Subject(s)
DNA Methylation/genetics , DNA, Mitochondrial/genetics , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/cytology , Animals , Becaplermin/pharmacology , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cell Respiration/drug effects , DNA (Cytosine-5-)-Methyltransferase 1/metabolism , DNA Methylation/drug effects , Female , Gene Expression Regulation/drug effects , Humans , Male , Mice, Inbred C57BL , Mitochondria/drug effects , Mitochondria/metabolism , Muscle, Smooth, Vascular/drug effects , Vascular Diseases/genetics , Vascular Diseases/pathologyABSTRACT
BACKGROUND: Abciximab is a widely used adjunctive therapy for acute coronary syndrome (ACS). However, the effect of intracoronary (i.c.) administration of abciximab on cardiovascular events remains unclear when compared with intravenous (i.v.) therapy. METHODOLOGY AND PRINCIPAL FINDINGS: We systematically searched the Medline, Embase, and Cochrane Central Register of Controlled Trials databases and reference lists of articles and proceedings of major meetings for obtaining relevant literature. All eligible trials included ACS patients who received either i.c. administration of abciximab or i.v. therapy. The primary outcome was major cardiovascular events, and secondary outcomes included total mortality, reinfarction, and any possible adverse events. Of 660 identified studies, we included 9 trials reporting data on 3916 ACS patients. Overall, i.c. administration of abciximab resulted in 45% reduction in relative risk for major cardiovascular events (RR; 95% confidence interval [CI], 24-60%), 41% reduction in RR for reinfarction (95% CI, 7-63%), and 44% reduction in RR for congestive heart failure relative to i.v. therapy (95% CI, 8-66%); however, compared to i.v. therapy, i.c. administration of abciximab had no effect on total mortality (RR, 0.69; 95% CI, 0.45-1.07). No other significant differences were identified between the effect of i.c. abciximab administration and i.v. therapy. CONCLUSIONS/SIGNIFICANCE: I.c. administration of abciximab can reduce the risk of major cardiovascular events, reinfarction, and congestive heart failure when compared with i.v. therapy.
