Abstract
BackgroundMetabolic remodeling plays a vital role in the development of heart failure. The trimetazidine can optimize fatty acid and glucose oxidation via inhibition of long-chain 3-ketoacyl CoA thiolase in the heart. So, trimetazidine commonly used in cardiovascular therapy as a myocardial metabolic drug. This study was conducted to assess the effects and mechanisms of trimetazidine on ketone body metabolism in heart failure rats.MethodsA rat model of heart failure was established by continuous subcutaneous injection of isoproterenol in 10 mg/kg/d. We examined body weight, heart weight index, and tested B-type natriuretic peptide by kit. We detected the structure and function of the heart. Hematoxylin-eosin staining and Masson’s trichrome staining was performed to assess myocardial tissue morphology. To evaluate apoptosis, we used Tunel staining. Metabolic substrate contents of glucose, free fatty acid, ketone bodies, lactic acid, and pyruvate and ATP levels in myocardial tissues were measured with the corresponding kit. We detected the levels of protein expressions related to myocardial substrate uptake and utilization by Western blot.ResultsTrimetazidine remarkably reduced the heart weight index and B-type natriuretic peptide levels. Besides, trimetazidine increased the level of blood pressure and decreased heart rate. Moreover, trimetazidine inhibited decreases in left ventricular ejection fraction and left ventricular fractional shortening. Further, trimetazidine decreased the levels of collagen volume fraction and promoted ATP production in myocardial tissues. Trimetazidine also reduced the levels of free fatty acid, ketone bodies, lactic acid, and increased glucose and pyruvate levels in myocardial tissues. Furthermore, trimetazidine markedly inhibited apoptosis. More importantly, the protein expression levels related to myocardial substrate uptake and utilization increased dramatically in the trimetazidine group. In particular, the protein expressions related to ketone body utilization were prominent.ConclusionsTrimetazidine could attenuate metabolic remodeling and improve cardiac function in heart failure rats. The potential mechanism for the cardioprotective effect of trimetazidine may be highly associated with its regulation of adenosine monophosphate-activated protein kinase, and peroxisome proliferator activated receptor α expressions. Along with the regulation, myocardial substrate utilization was improved, especially the utilization of ketone bodies.
Highlights
Heart failure (HF), with its notable morbidity and mortality, is directly related to significant health and economic burdens worldwide (Benjamin et al, 2017)
These results prove that TMZ attenuates the effect of ISO in inducing HF
Treated with TMZ can remarkably prevent the accumulation of the acidic metabolite and improve insufficiencies of adenosine triphosphate (ATP), glucose, and pyruvate. These results indicate that TMZ attenuated the histopathology alterations and improved the utilization of cardiac metabolism substrate in ISO-induced HF rats
Summary
Heart failure (HF), with its notable morbidity and mortality, is directly related to significant health and economic burdens worldwide (Benjamin et al, 2017). Some substrates can be used for energy metabolism in the heart, including free fatty acids (FFA), carbohydrates (glucose and lactate), ketone bodies, and amino acid (Kolwicz et al, 2016). The failing heart could improve ATP production by reducing cardiac fatty acids utilization and an increase in glucose use. The ketone body utilization behaves as a potential benefit, few Abbreviations: HF, Heart failure; FFA, free fatty acids; ATP, adenosine triphosphate; KB, ketone body; TMZ, Trimetazidine; ISO, isoproterenol; AMPK, adenosine monophosphate-activated protein kinase; PPARa, peroxisome proliferator activated receptora; LDH, lactate dehydrogenase; GLUT4, glucose transporter 4; p-ACC, phospho-acetyl-CoA carboxylas; HMGCS2, 3-hydroxy-3methylglutaryl-CoA2; MCT1, monocarboxylate transporter 1; BDH1,bhydroxybutyrate dehydrogenase 1; p-AMPK, phospho-AMPK; CPT1, carnitine palmitoyltransferase 1; ACAT1, acetoacetyl-CoA thiolase 1; OXCT1(SCOT1), succinyl-CoA:3-ketoacid-CoA transferase; BNP, B-type Natriuretic Peptide; CVF, Collagen volume fraction; TUNEL, TdT-mediated dUTP Nick-End Labeling; PBS, phosphate buffer saline; DAPI, 4’,6-diamidino-2-phenylindole. This study was conducted to assess the effects and mechanisms of trimetazidine on ketone body metabolism in heart failure rats
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