Exogenous supplementation with N-acetyl-glutamate or fumarate significantly improved cardiac function and reduced fibrosis after MI in mice by limiting fibroblast mitochondrial ATP production.
Does modulation of the NAcGlu/ASL/fumarate axis by SGLT2 inhibitors reduce cardiac fibrosis and improve cardiac function post-MI in preclinical models?
SGLT2 inhibitors limit post-MI cardiac fibrosis by modulating the NAcGlu/ASL/fumarate axis, which suppresses the TCA cycle and reduces ATP production in cardiac fibroblasts.
Abstract Aims Cardiac fibrosis, a common pathological outcome of various heart diseases including myocardial infarction (MI), is primarily driven by the activation and trans-differentiation of cardiac fibroblasts which demand substantial ATP for energy. Although sodium-glucose cotransporter 2 (SGLT2) inhibitors such as dapagliflozin (DAPA) have been shown to improve outcomes in heart failure, their direct impact on cardiac fibrosis, particularly through the modulation of fibroblast energy metabolism remains unexplored. Methods and results We employed an integrated strategy combining metabolomics and metabolic flux analysis to investigate metabolic reprogramming in cardiac fibroblasts under ischaemic conditions. Our findings confirmed that treatment with an SGLT2 inhibitor confers anti-fibrotic benefits post-MI. Multi-omics analysis identified a key metabolic pathway modulated in fibroblasts from SGLT2 inhibitor-treated mice under ischaemia: the conversion of N-acetyl-glutamate (NAcGlu) to fumarate, catalysed by argininosuccinate lyase (ASL). This pathway serves as a metabolic bridge linking the urea cycle to the tricarboxylic acid (TCA) cycle. Exogenous supplementation with either NAcGlu or fumarate significantly improved cardiac function and reduced fibrosis after MI. In contrast, targeted deletion of ASL in activated cardiac fibroblasts impaired cardiac performance, even with NAcGlu supplementation. Mechanistically, we found that fumarate accumulation under stress presses the TCA cycle in cardiac fibroblasts, resulting in reduced ATP production. Conclusions These findings identify the NAcGlu/ASL/fumarate axis as an important regulator of fibroblast metabolism and trans-differentiation during ischaemic stress. Our data are consistent with a model in which targeting key metabolites (NAcGlu, fumarate) or enzymes (ASL) in the urea cycle pathway of cardiac fibroblasts may point to a potential therapeutic strategy to combat adverse cardiac fibrosis following MI.
This basic science paper is notable for its deep dive into the metabolic pathways influencing cardiac fibrosis after a heart attack. The identification of fumarate's role offers a novel perspective on potential anti-fibrotic therapies, a significant area of unmet need in post-MI care.
Zhao et al. (Wed,) conducted a other in Cardiac fibrosis post-myocardial infarction. SGLT2 inhibitor (dapagliflozin), N-acetyl-glutamate, or fumarate was evaluated on Cardiac fibrosis and cardiac function. Exogenous supplementation with N-acetyl-glutamate or fumarate significantly improved cardiac function and reduced fibrosis after MI in mice by limiting fibroblast mitochondrial ATP production.