A Study On The Relationship Between Peroxisome Proliferator-activated Receptor γ And Cardiac Hypertrophy

In response to a variety of mechanical, hemodynamic, hormonal, and pathologic stimuli, the heart adapts to increased demands for cardiac work by increasing muscle mass through the initiation of a hypertrophic response. Cardiac hypertrophy i?observed in various cardiovascular diseases such as hypertension, myocardial infarction, valvular heart diseases, and hypertrophic cardiomyopathy. Clinical studies have demonstrated that cardiac hypertrophy is not only an adaptational state before heart failure but is an independent risk factor for ischemia, arrhythmia, and sudden death. Peroxisome proliferator-activated receptors (PPARs) are world wide researched transcription factors in recent years as a member of the nuclear receptor superfamily, and play a key role in various disorders, such as lipid metabolism, diabetes mellitus, inflammation and even some tumors. More recently, many reports indicate another novel aspect of PPARs in various cardiovascular diseases. However, further studies will be needed to explore whether PPARy are molecules of anti-hypertrophic signaling and participate in the negative regulation process of cardiac hypertrophy.In this study, we investigated the role of peroxisome proliferator-activated receptor Y in cardiac hypertrophy in vitro. Hypertrophy in neonatal rat cardiac myocytes (MC) and cardiac nonmyocytes (NMC) was established with angiotensin II (Ang II). mRNA expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was measured by reverse transcription-polymerase chain reaction (RT-PCR), proliferation of NMC was estimated with MTT assay and 3H-TdR uptake, the surface area of MC was analyzed by the aid of NIH Image J software, and the synthetic rate of protein in MC was detected by 3H-leucine incorporation. In the condition of hypertrophy, increases of surface area of MC, mRNA expression of ANP and BNP and 3H-leucine incorporation in MC and an increase of proliferation in NMC were detected, but no changes in mRNA expression of ANP and BNP in NMC. 15-deoxy-A12,14prostaglandin h (15d-PGJ2) and pioglitazone, the representativenatural and synthesized PPARy activators, inhibited the changes above and reduced mRNA expression of ANP and BNP in NMC in a concentration - dependent manner. These results suggest that 15d-PGJ2 and pioglitazone inhibit cardiac hypertrophy induced by angiotensin â…¡ in vitro and PPAR Y -dependent pathway may participate in the negative regulation process of cardiac hypertrophy.To confirm PPAR y -dependent pathway is involved in the inhibition of cardiac hypertrophy, a segment of sequence containing PPRE from the promoter of rat acyl-CoA oxidase (AGO) gene was amplified by PCR, and subcloned into pGL3 basic vector. Thus, the recombinant vector PPRE-pGL3 was obtained. With it, the rat non-cardiac myocytes were transiently transfected in or not presence of pSG5-PPAR Y expression plasmid. Luciferase activities were measured using dual-luciferase reporter assay reagent according to the instruction in the kit. The results indicated the relative luciferase expression markedly increased in the co-transfected group than that in the non co-transfected group. With the stimulation of ISd-PGJa or pioglitazone, the relative luciferase expression was also markedly increased in a concentration -dependent manner in both the conditions of co-transfection with and without pSG5-PPAR Y , as compared with vehicle group.In conclusion, it is suggest that PPAR Y -dependent pathway is critically involved in the inhibition of cardiac hypertrophy in vitro.