Cardiac Metabolism and MiRNA Interference

Abstract

The aberrant increase in cardio-metabolic diseases over the past couple of decades has drawn researchers' attention to explore and unveil the novel mechanisms implicated in cardiometabolic diseases. Recent evidence disclosed that the derangement of cardiac energy substrate metabolism plays a predominant role in the development and progression of chronic cardiometabolic diseases. Hence, in-depth comprehension of the novel molecular mechanisms behind impaired cardiac metabolism-mediated diseases is crucial to expand treatment strategies. The complex and dynamic pathways of cardiac metabolism are systematically controlled by the novel executor, microRNAs (miRNAs). miRNAs regulate target gene expression by either mRNA degradation or translational repression through base pairing between miRNA and the target transcript, precisely at the 3' seed sequence and conserved heptametrical sequence in the 5' end, respectively. Multiple miRNAs are involved throughout every cardiac energy substrate metabolism and play a differential role based on the variety of target transcripts. Novel theoretical strategies have even entered the clinical phase for treating cardiometabolic diseases, but experimental evidence remains inadequate. In this review, we identify the potent miRNAs, their direct target transcripts, and discuss the remodeling of cardiac metabolism to cast light on further clinical studies and further the expansion of novel therapeutic strategies. This review is categorized into four sections which encompass (i) a review of the fundamental mechanism of cardiac metabolism, (ii) a divulgence of the regulatory role of specific miRNAs on cardiac metabolic pathways, (iii) an understanding of the association between miRNA and impaired cardiac metabolism, and (iv) summary of available miRNA targeting therapeutic approaches.

Keywords: ATP generation; cardiac metabolism; cardiometabolic disease; fatty acid metabolism; glucose metabolism; miRNA targeting therapy; miRNAs.

Figure 1

Role of miRNAs in cardiac energy substrate metabolism. (A) miRNA-regulated glucose transportation into cardiomyocytes by GLUT1 or GLUT4. (B) miR-125b and miR34a regulates the hexokinase activity. (C) Glucose 6- phosphate undergoes glycogen synthesis under the regulation of miR26, miR378, miR29c-3p, miR144-3p, and miR126. (D) Glucose metabolism by glycolysis under the regulation of miRNAs. (E) The resulting pyruvate is converted to acetyl-CoA, and (F) enters into the TCA cycle to produce reducing equivalents. (G) Free fatty acids enter into the cardiomyocytes by miRNAs and form the fatty acyl- CoA (H) to be involved in β-oxidation to form acetyl-CoA (I). (J) BCAA was transported into mitochondria, oxidizing to form acetyl-CoA (K). (L) After the TCA cycle, the reducing equivalents undergo oxidative phosphorylation to generate chemical energy, ATP. MCT4: Monocarboxylic anion transporter 4; G-6-P: Glucose -6-phosphate; LDH: lactate dehydrogenase; FAT: Fatty acid translocase, FAT: Fatty acid translocase, FACS: Fatty-acyl-CoA synthase; CPT1: carnitine palmitoyltransferase. BCAT: Branched-chain α ketoacids; BCAT: Branched-chain amino acid aminotransferase.