Cardiometabolism as an Interlocking Puzzle between the Healthy and Diseased Heart: New Frontiers in Therapeutic Applications

Abstract

Cardiac metabolism represents a crucial and essential connecting bridge between the healthy and diseased heart. The cardiac muscle, which may be considered an omnivore organ with regard to the energy substrate utilization, under physiological conditions mainly draws energy by fatty acids oxidation. Within cardiomyocytes and their mitochondria, through well-concerted enzymatic reactions, substrates converge on the production of ATP, the basic chemical energy that cardiac muscle converts into mechanical energy, i.e., contraction. When a perturbation of homeostasis occurs, such as an ischemic event, the heart is forced to switch its fatty acid-based metabolism to the carbohydrate utilization as a protective mechanism that allows the maintenance of its key role within the whole organism. Consequently, the flexibility of the cardiac metabolic networks deeply influences the ability of the heart to respond, by adapting to pathophysiological changes. The aim of the present review is to summarize the main metabolic changes detectable in the heart under acute and chronic cardiac pathologies, analyzing possible therapeutic targets to be used. On this basis, cardiometabolism can be described as a crucial mechanism in keeping the physiological structure and function of the heart; furthermore, it can be considered a promising goal for future pharmacological agents able to appropriately modulate the rate-limiting steps of heart metabolic pathways.

Current Status and Future Perspectives on Therapeutic Potential of Apigenin: Focus on Metabolic-Syndrome-Dependent Organ Dysfunction

“…Notably, HIF-lα, strongly expressed in hypertrophied hearts, can be inhibited by apigenin; this finding, together with the ability of apigenin to selectively modulate PPARγ, corroborates the important role of apigenin in affecting blood pressure and glucolipid metabolism. In this regard, a recent study [105] examined the chronic effects of apigenin in a rat model of cardiac hypertrophy induced by renovascular hypertension, in which selective metabolic changes in myocardial energy utilization, based on the switch from fatty acids to glucose, occur [106]. The authors highlighted the beneficial contribution of apigenin in improving hypertensive cardiac hypertrophy and abnormal myocardial glucolipid metabolism by reducing myocardial HIF-1α expression and upregulating the expressions of myocardial PPARγ and its target genes, glycerol-3-phosphate acyltransferase genes (GPAT) and glucose transporter (GLUT-4) [105].…”

MCC950, a Selective NLRP3 Inhibitor, Attenuates Adverse Cardiac Remodeling Following Heart Failure Through Improving the Cardiometabolic Dysfunction in Obese Mice

“…The current findings suggest that MCC950 promoted the expression of CD36 and CPT1β after TAC surgery, implying that MCC950 can promote FA transport and oxidation in the hearts of obese mice with HF. Furthermore, CPT1β is inhibited by malonyl-CoA, the carboxylation product of acetyl-CoA, which is produced by the action of ACC and decarboxylated by MCD ( 39 ). In this study, MCC950 increased the phosphorylation level of ACC and increased the expression of MCD, thereby reducing the production of malonyl-CoA and promoting its degradation, ultimately increasing the level of CPT1β.…”

“…GLUT4 is insulin-sensitive and is the major isoform in adult myocardium. GLUT1 is insulin-independent and mainly expressed in the fetal heart ( 39 ). The GLUT4/GLUT1 ratio has been reported to be reduced in patients with LV hypertrophy ( 42 ).…”

Mitochondrial Determinants of Anti-Cancer Drug-Induced Cardiotoxicity

“…Energy supply in cardiac cells. To cope with the energy demands of the heart, mitochondria produce ATP from a wide range of substrates, such as carbohydrates, fatty acids, amino acids and ketone bodies; however, under basal conditions, energy is mainly drawn from fats (60-90% of cardiac energy supply) [1]. Specifically, while fatty acids (FAs) are directly subjected to β-oxidation in the mitochondria, glucose is preliminarily subjected to glycolysis in the cytosol to produce pyruvate, which in turn is transferred to the mitochondria for oxidation.…”

“…Despite the great energy consumption needed for contraction and ion transport, the human heart is characterized by a limited content of endogenous high-energy phosphate, able to support cardiac activity only for a very short time [1]. For this reason, adenosine triphosphate (ATP) is constantly produced, especially by mitochondria which, beside representing one third of myocyte volume, account for more than 95% of the cardiac ATP [2].…”