A Study On Effects Of ERK1/2 / PPARα / SCAD Signal Pathway On Physiological And Pathological Cardiomyocyte Hypertrophy

ObjectiveShort-chain acyl-Co A dehydrogenase(SCAD) is a key enzyme in fatty acid oxidation. In the present study we aim to investigate the changes of SCAD between pathological and physiological cardiomyocyte hypertrophy. We also investigate different regulations of ERK1/2/PPARα/SCAD signal pathways between pathological and physiological cardiomyocyte hypertrophy. We aim to explore a new target to prevent the development of pathological cardiac hypertrophy. Methods 1. The neonatal rat cardiomyocytes induced by Insulin-like growth factors 1( IGF-1) andPhenylephrine( PE) were used as the model of physiological cardiac hypertrophy andpathological cardiac hypertrophy. Surface area of cardiomyocytes, expression ofp-ERK1/2, PPARα and SCAD, activity of SCAD, free fatty acid content and ATP contentin cardiomyocytes were mesured. 2. Cells were pretreated with PPARα inhibitor GW6471 and PPARα activator fenofibratefor 30 min, then treated by IGF-1 and PE for 24 h. Surface area of cardiomyocytes,expression of p-ERK1/2, PPARα and SCAD, activity of SCAD, free fatty acid contentand ATP content in cardiomyocytes were mesured. 3. Cells were pretreated with ERK1/2 activator EGF and ERK1/2 inhibitor PD98059 for30 min, then treated by IGF-1 and PE for 24 h. Surface area of cardiomyocytes, expression of p-ERK1/2, PPARα and SCAD, activity of SCAD, free fatty acid content and ATP content in cardiomyocytes were mesured. Results 1. Compared with the control group, the surface area of cardiomyocytes induced by IGF-1 and PE were both increased. Meanwhile, the m RNA expression of ANF and BNP, two important marker genes of myocardial hypertrophy, was significantly higher in the PE- or IGF-1-treated group than in the control group. For the marker genes of pathological cardiac hypertrophy, the expression of α-Sk A was significantly higher in the PE-treated group, however, no changes in the IGF-1-treated group, which indicated that two cardiomyocyte hypertrophy models were successfully established. 2. Compared with the control group, cardiomyocytes treated with IGF-1 had an increasedexpression of SCAD and PPARα, an increased activity of SCAD, a decreased expression of p-ERK1/2, a decreased level of free fatty acids and an increased level ATP. However, cardiomyocytes treated with PE had a decreased expression of SCAD and PPARα, a decreased activity of SCAD, an increased expression of p-ERK1/2, an increased level of free fatty acids and an increased ATP level. 3. Compared with the control group, IGF-1 treatment significantly increased cell surface area, m RNA and protein expression of PPARα, expression and activity of SCAD and ATP level, but decreased free fatty acids content. Pretreatment with GW6471 significantly abrogated the effects in IGF-1-treated cardiomyocytes compared with the cells treated with IGF-1 alone. However, it showed the contrary results in PE-induced hypertrophy to IGF-1-treated group except cell surface area. Furthermore, pretreatment with significantly inhibited those effects of cardiomyocytes treated with PE. 4. Pretreatment with EGF obviously attenuated the effects of IGF-1, such as the increased level of cell surface area, m RNA and protein expression of PPARα and SCAD, activity of SCAD and ATP content, the decreased protein level of phospho-ERK1/2 and the ecreased level of free fatty acids content were reversed. However, PE treatment had contrary effects to IGF-1, and pretreatment with PD98059 obviously inhibited those effects in PE-induced cardiomyocytes. ConclusionSCAD has different changes between pathological and physiological cardiomyocyte hypertrophy. ERK1/2/PPARα/SCAD signal pathways play different roles in pathological and physiological cardiomyocyte hypertrophy. SCAD may be as a new marker genes of two different cardiomyocyte hypertrophy and a new target to prevent the development of pathological cardiac hypertrophy.