Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice

Abstract

Increasing evidence indicates the involvement of myocardial oxidative injury and mitochondrial dysfunction in the pathophysiology of heart failure (HF). Alpha-ketoglutarate (AKG) is an intermediate metabolite of the tricarboxylic acid (TCA) cycle that participates in different cellular metabolic and regulatory pathways. The circulating concentration of AKG was found to decrease with ageing and is elevated after acute exercise and resistance exercise and in HF. Recent studies in experimental models have shown that dietary AKG reduces reactive oxygen species (ROS) production and systemic inflammatory cytokine levels, regulates metabolism, extends lifespan and delays the occurrence of age-related decline. However, the effects of AKG on HF remain unclear. In the present study, we explored the effects of AKG on left ventricular (LV) systolic function, the myocardial ROS content and mitophagy in mice with transverse aortic constriction (TAC). AKG supplementation inhibited pressure overload-induced myocardial hypertrophy and fibrosis and improved cardiac systolic dysfunction; in vitro, AKG decreased the Ang II-induced upregulation of β-MHC and ANP, reduced ROS production and cardiomyocyte apoptosis, and repaired Ang II-mediated injury to the mitochondrial membrane potential (MMP). These benefits of AKG in the TAC mice may have been obtained by enhanced mitophagy, which cleared damaged mitochondria. In summary, our study suggests that AKG improves myocardial hypertrophy remodelling, fibrosis and LV systolic dysfunction in the pressure-overloaded heart by promoting mitophagy to clear damaged mitochondria and reduce ROS production; thus, AKG may have therapeutic potential for HF.

Comparative Analysis of Right Ventricular Metabolic Reprogramming in Pre-clinical Rat Models of Severe Pulmonary Hypertension-induced Right Ventricular Failure

“…α -KG supplementation has been shown to improve cardiac contractile dysfunction in transverse aortic constriction (TAC) mice by attenuating pressure overload-induced cardiac hypertrophy and fibrosis. Further, α -KG exerts cardioprotective effects in TAC-induced failing myocardium by: 1) reducing ROS production and oxidative stress, 2) inhibiting cardiomyocyte apoptosis, 3) promoting autophagy and mitophagy, and 4) improving mitochondrial membrane potential 64,65 .…”

“…In the current study, we also identified tricarboxylic acid (TCA) cycle (citric acid cycle) as one of the top common dysregulated metabolic pathways in RV of MCT and Su/Hx rats (Figure 8). a-ketoglutarate (a-KG), as a crucial intermediate metabolite of TCA cycle, regulates ATP production and mitochondrial energy homeostasis [62][63][64] . Interestingly we found a significant decrease in a-KG in both MCT and Su/Hx rats (Figure 4C).…”

Mitochondria in Pathological Cardiac Hypertrophy Research and Therapy

“…A very recent study has found that external supplementation of alpha-ketoglutarate (AKG), an intermediate metabolite of the tricarboxylic acid cycle, effectively suppressed transverse aortic constriction (TAC)-induced cardiac hypertrophy and improved heart function ( 82 ). The cardio-protective roles of AKG may be achieved by promoting mitophagy, which helped to remove damaged mitochondria and reduce ROS production ( 82 ). Allyl Methyl Sulfide (AMS) intervention also exerted protective effects on TAC-induced cardiac hypertrophy.…”

Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases

“…GPR99 KO mice show a significant increase in cardiac hypertrophy decrease in cardiac shortening and ejection fraction following transverse aortic constriction [ 358 , 359 ]. Neonatal rat cardiomyocytes overexpressing OXGR1 show reduced phenylephrine-induced cardiomyocyte hypertrophy [ 360 ].…”