malonyl-coenzyme-a and Hypertension

Hypertension and kidney disease have been repeatedly associated with genomic variants and alterations of lysine metabolism. Here, we combined stable isotope labeling with untargeted metabolomics to investigate lysine's metabolic fate in vivo. Dietary

Topics: Albumins; Animals; Carbon; Disease Models, Animal; Hypertension; Kidney; Lysine; Malonyl Coenzyme A; Rats

Development of heart failure is known to be associated with changes in energy substrate metabolism. Information on the changes in energy substrate metabolism that occur in heart failure is limited and results vary depending on the methods employed. Our aim is to characterize the changes in energy substrate metabolism associated with pressure overload and ischaemia-reperfusion (I/R) injury.. We used transverse aortic constriction (TAC) in mice to induce pressure overload-induced heart failure. Metabolic rates were measured in isolated working hearts perfused at physiological afterload (80 mmHg) using (3)H- or (14)C-labelled substrates. As a result of pressure-overload injury, murine hearts exhibited: (i) hypertrophy, systolic, and diastolic dysfunctions; (ii) reduction in LV work, (iii) reduced rates of glucose and lactate oxidations, with no change in glycolysis or fatty acid oxidation and a small decrease in triacylglycerol oxidation, and (iv) increased phosphorylation of AMPK and a reduction in malonyl-CoA levels. Sham hearts produced more acetyl CoA from carbohydrates than from fats, whereas TAC hearts showed a reverse trend. I/R in sham group produced a metabolic switch analogous to the TAC-induced shift to fatty acid oxidation, whereas I/R in TAC hearts greatly exacerbated the existing imbalance, and was associated with a poorer recovery during reperfusion.. Pressure overload-induced heart failure and I/R shift the preference of substrate oxidation from glucose and lactate to fatty acid due to a selective reduction in carbohydrate oxidation. Normalizing the balance between metabolic substrate utilization may alleviate pressure-overload-induced heart failure and ischaemia.

Topics: Acetyl Coenzyme A; Animals; Echocardiography; Glucose; Glucose Transporter Type 4; Heart Failure; Hypertension; Hypertrophy, Left Ventricular; Lactic Acid; Male; Malonyl Coenzyme A; Mice; Mice, Inbred C57BL; Myocardial Reperfusion Injury; Systole

CD36, a multifunctional protein, is involved in cardiac long chain fatty acid (LCFA) metabolism and in the etiology of heart diseases, yet the functional impact of Cd36 gene variants remains unclear. In 7-week-old spontaneously hypertensive rats (SHR), which, like humans, carry numerous mutations in Cd36, we tested the hypothesis that their restricted cardiac LCFA utilization occurs prior to hypertrophy due to defective CD36 post-translational modifications (PTM), as assessed by ex vivo perfusion of (13)C-labeled substrates and biochemical techniques. Compared to their controls, SHR hearts displayed a lower (i) contribution of LCFA to β-oxidation (-40%) and triglycerides (+2.8 folds), which was not explained by transcriptional changes or malonyl-CoA level, a recognized β-oxidation inhibitor, and (ii) membrane-associated CD36 protein level, but unchanged distribution. Other results demonstrate alterations in CD36 PTM in SHR hearts, specifically by N-glycosylation, and the importance of O-linked-β-N-acetylglucosamine for its membrane recruitment and role in LCFA use in the heart.

Topics: Animals; CD36 Antigens; Fatty Acids; Fluorescent Antibody Technique; Glycoproteins; Glycosylation; Heart; Hypertension; Immunoblotting; Malonyl Coenzyme A; Mutation; Organ Culture Techniques; Oxidation-Reduction; Protein Processing, Post-Translational; Rats; Rats, Inbred SHR; Rats, Wistar; Triglycerides