Effects Of Carvedilol On Fatty Acid Oxidation And Myocardial Remodeling And Its Mechanism During The Development Of Cardiac Hypertrophy Induced By Coarctation Of Abdominal Aorta

Background and Objectives The fetal heart derives energy largely from the oxygen-sparing catabolism of glucose and lactate, and it transform to reliance on fatty acids postnatal immediately. Recent studies have shown that during the development of hypertrophy or heart failure occurred, the heart reverts to reliance on glycolysis as the primary pathway for energy production: a recapitulation of fetal energy metabolism. It would allow ATP production at a lower oxygen consumption cost, but may cause energy starvation in the heart. Clinical trials have shown that carvedilol offers a high degree of cardiac protection in patients with congestive heart failure. But little is known about the role of carvedilol on cardiac energy metabolism as yet. The purse of this study is to delineate the molecular regulatory events involved in "the recapitulation of fetal energy metabolism", and left ventricular remodeling in pressure overload-induced hypertrophy, and to explore the molecular mechanism of cardiac protection provided from treatment of carvedilol.Material and Methods To study associated pathologic and pathophysiologic changes of myocardial hypertrophy, the male Wistar rats of myocardial hypertrophy induced by coarctation of abdominal aorta (CAA) were randomized into 4 groups of 12 each: 2-week group (CAA2W group), 4-week group (CAA4W group), 8-week group (CAA8W group), and 16-week group (CAA16W group). To evaluate the effects of drugs intervention for 12 weeks, the survival 24 rats of 4-weeks after operation were randomized into 3 groups of 8 each: Carvedilol group (CAR group, 30mg.kg-1day-1), Metoprolol group (MET group,50mg.kg-1day-1), and Terazosin group (TER group, 2mg.kg-1day-1). Additional rats(n=12) underwent abdominal cavity incision without ligation to serve as age-matched sham operated controls (SH). Heart rate (HR), leftventricular end diastolic pressure (LVEDP), left ventricular end systolic pressure (LVESP), mean arterial pressure (MAP) and left ventricular pressure maximal rising and declining velocities (±dp/dtmax), and the ratio of left ventricular weight to body weight (LVW/BW) and the ratio of right ventricular weight to body weight (RVW/BW), and level of free fatty acid(FFA)both in blood serum and myocardium were measured. RT-PCR analysis of the expressions of mRNA of muscle carnitine palmitoyltransferase I (M-CPT-I), medium chain acyl-CoA dehydrogenase (MCAD), peroxisome proliferator-activated receptor ( (PPAR(), muscle LIM protein (MLP), (/(- myosin heavy chain (MHC), Colligin and collagen type I/III were observed. The proteins expressions of Colligin, MLP, PPAR( and collagen type I/III were analyzed by Western blot.Results Compared with SH group, MAP was significantly increased, while －dp/dtmax was decreased in all CAA groups. LVM/BW, LVEDP, LVSP and＋dp/dtmax were increased in CAA4W, CAA8W and CAA16W groups, changes of all of these parameters in CAA16W group were most significant. RVW/BW is no change in all CAA groups. There were progressive increases in FAA both in blood serum and myocardium in all CAA groups, accompanied with gradual downregulation of gene expressions of rate-limiting enzyme ( M-CPT-I), key enzyme of fatty acid (MCAD) and PPAR( in LV, while protein expression of PPAR( began to be decreased till 8-week after operation. The gene expressions of M-CPT-I and MCAD in LV were upregulated and FFA accumulation were significantly down-regulated in CAR group, comparing with CAA16W group. MLP mRNA was decreased in CAA8W and CAA16W groups, while the changes of MLP protein expression were no significant in all CAA groups. Carvedilol (at 30mg.kg-1day-1) was more effective in reducing the left ventricular hypertrophy than metoprolol (at 50mg.kg-1day-1), and without significant changes in TER group. Carvedilol intervention for 12 weeks suppressed the increasing of Colligin gene/protein and collagen type I/III proteins and the decreasing of the ratio of (/(-MHC mRNA significantly in CAA16W group, but the effects were mild both in MET and TER groups.Conclusions 1) Accumulat...