The benefit of medium-chain triglyceride therapy on the cardiac function of SHRs is associated with a reversal of metabolic and signaling alterations.
The spontaneously hypertensive rat (SHR) is a model of cardiomyopathy that displays a genetic defect in cardiac fatty acid (FA) translocase/CD36, a plasma membrane long-chain FA transporter. Therapy with medium-chain FAs, which do not require CD36-facilitated transport, has been shown to improve cardiac function and hypertrophy in SHRs despite persistent hypertension. However, little is known about the underlying molecular mechanisms. The aim of this study was to document the impact of medium-chain triglyceride (MCT) therapy in SHRs on the expression level and activity of metabolic enzymes and signaling pathways. Four-week-old male SHRs were administered MCT (SHR-MCT) or long-chain triglyceride (SHR-LCT) for 16 wk. We used Wistar-Kyoto (WKY) rats as controls (WKY-MCT and WKY-LCT). The SHR-MCT group displayed improved cardiac dysfunction [as assessed by left ventricular (LV) end-diastolic pressure and the positive and negative first derivatives of LV pressure/P value], a shift in the beta-myosin heavy chain (MHC)-to-alpha-MHC ratio, and cardiac hypertrophy compared with the SHR-LCT group without an effect on blood pressure. Administration of MCT of SHRs reversed the LCT-induced reduction in the cardiac FA metabolic enzymatic activities of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and medium-chain acyl-CoA dehydrogenase (MCAD). In the SHR-MCT group, the protein expression and transcriptional regulation of myocardial peroxisome proliferator-activated receptor-alpha, which regulates the transcription of LCHAD and MCAD genes, corresponded to the changes seen in those enzymatic activities. Furthermore, MCT intake caused an inhibition of JNK activation in SHR hearts. Collectively, the observed changes in the myocardial activity of metabolic enzymes and signaling pathways may contribute to the improved cardiac dysfunction and hypertrophy in SHRs following MCT therapy.
Iemitsu
Motoyuki
M
Institute of Clinical Medicine, Univ. of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Shimojo
Nobutake
N
Maeda
Seiji
S
Irukayama-Tomobe
Yoko
Y
Sakai
Satoshi
S
Ohkubo
Takeshi
T
Tanaka
Yukihisa
Y
Miyauchi
Takashi
T
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism; D042964:Acyl-CoA Dehydrogenase / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D018955:CD36 Antigens / Q000378:metabolism; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects* / Q000235:genetics; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic; D014280:Triglycerides / Q000494:pharmacology* / Q000627:therapeutic use; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D024723:Ventricular Myosins / Q000378:metabolism; D017725:Ventricular Pressure / Q000187:drug effects
D018955:CD36 Antigens; C008132:Cd36 protein, rat; C000594638:MYH7 protein, rat; D047493:PPAR alpha; D012333:RNA, Messenger; D014280:Triglycerides; D015094:3-Hydroxyacyl CoA Dehydrogenases; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase; D042964:Acyl-CoA Dehydrogenase; D048031:JNK Mitogen-Activated Protein Kinases; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains