MicroRNA-214Inhibits Cardiac Rmodeling In Mouse Models Of Cardiac Pressure Overload

Objective: Cardiovascular disease leads to the highest mortality in theworld especially in the developed countries. Cardiac pressure overload likehypertension results in ventricular hypertrophy, fibrosis and makes cardiacfunction worse and leads to heart failure. Researchers have found that severalmiRNAs expressed aberrantly in impaired cardiomyocytes, it suggests thatthese miRNAs may play an important role during the process ofcardiomyocytes injury. In our previous study, we have found that miR-214hasaberrant expression in acute myocardial infarction rats cardiomyocyts, and ithas been demonstrated that miR-214plays an important role duringmyocardial infarction. We also found that over-expression of miR-214protectsthe cardiomyocytes injury induced by H2O2. In this study,we applied awell-established cardiac hypertrophy mouse model by transverse aorticconstriction(TAC) which results in cardiac pressure overload. And theexpression levels of miR-214were regulated by using apre-miR-214(Ad-miR-214) and a miR-214inhibitor (Ad-anti-miR) wereused to up regulated and down regulated the expression levels of miR-214.Therefore we can observe the function of miR-214in cardiac remodeling.Methods: we applied a well-established cardiac hypertrophy mousemodel by transverse aortic constriction(TAC). A pre-miR-214was used toup regulated the expression levels of miR-214. Mice were randomly dividedinto three groups: a cardiac hypertrophy model group with Ad-GFP (Ad-GFPgroup, n=24), an cardiac hypertrophy model group with Ad-miR-214(Ad-miR-214group, n=24) and a sham-surgery group(n=24). qRT-PCR wasused to determine the miR-214levels in cardiac tissue. Changes inhemodynamic parameters, including the heart rate(HR), the left ventricularend-diastolic pressure (LVEDP), the left ventricular systolic pressure (LVSP), the maximal rate of rise in blood pressure in the ventricular chamber (+dP/dtmax) and the maximal rate of decline in blood pressure in the ventricularchamber (-dP/dtmax) were recorded at8weeks after TAC surgery.Histological diagnosis was achieved by hematoxylin and eosin (H&E). Leftventricular (LV) dimensions, HW/BW(heart weight/body weight), collagentype Ⅰ, collagen type Ⅲ, ANP,β-MHC were measured. Flow cytometry wasperformed to examine the cell apoptosis.In another independent experiment, Kunming mice were randomly dividedinto2groups: the control group and the Ad-anti-miR group. miR-214inhibitorwas transfected into the mice of the Ad-anti-miR group via tail vein injectionwhile the mice in the control group injected Ad-GFP in order to make a furtherunderstanding of miR-214. Same detections as described were conducted at8weeks after transfection.Results:①Compared with sham group, the relative expression ofmiR-214increased significantly8weeks after TAC surgery(P<0.01).②AndmiR-214levels were also detected at4days and8weeks after transfection.Compared with control group, miR-214was up-regulated inAd-miR-214group and down-regulated significantly in Ad-anti-miR group(P<0.01).③Inthe Ad-miR-214group, LV dimensions, HW/BW, collagen type Ⅰ, type Ⅲ,ANP,β-MHC all significantly decreased compared with the Ad-GFP group.④A t8weeks after TAC surgery, the Ad-miR-214significantly improvedLVSP, LV+dp/dtmax, LV dp/dtmin(P<0.01), and decreased heart rate (HR)and LVEDP compared with the Ad-GFP group(P<0.01).⑤Compared with theAd-GFP, the cell apoptotic rate significantly decreased in the Ad-miR-214group.⑥In another independent experiment, similar detections wereconducted, and there was no significant difference between the Ad-anti-miRgroup and the control group.Conclusions: Ad-miR-214improves LV remodeling and suggesting thepossible mechanism by which ad-miR-214inhibits cardiac hypertrophy,fibrosis and decreases the apoptosis of myocardial cells induced by cardiacpressure overload.