bims-hafaim 2026-07-26 papers

Eur J Pharmacol. 2026 Jul 24. pii: S0014-2999(26)00658-8. [Epub ahead of print] 179176

Canagliflozin improves early-stage cardiac hypertrophy and energy metabolism in TAC mice.

Yumei Luo, Wanlin Peng, Cen Su, Yuan Chen, Dong Li, Yuqi Deng, Yuanna Ling, Wei Ouyang.

Early intervention in cardiac hypertrophy helps delay heart failure, but optimal intervention strategies remain unclear. We previously showed that cardiac energy metabolism changes dynamically during early cardiac hypertrophy. As a sodium-glucose cotransporter 2 inhibitor, canagliflozin (CANA) lowers blood glucose and modulates cardiac metabolic dysfunction. In this study, we examined the effects of CANA on early-stage cardiac hypertrophy in a transverse aortic constriction model using wild-type male C57BL/6J mice and investigated the underlying molecular mechanisms. CANA attenuated cardiac remodeling in TAC mice, reducing cardiomyocyte cross-sectional area, HW/BW ratio, and HW/TL ratio at day 7, and further decreasing left ventricular mass, wall thickness, and myocardial fibrosis at day 14. Furthermore, 18F-FDG micro-PET/CT imaging revealed stage-dependent regulation of myocardial glucose uptake by CANA, with increased uptake at day 7 and decreased uptake at day 14. Functional metabolic assays showed that CANA enhanced cardiac ATP production and fatty acid oxidation activity. Consistently, western blot analysis indicated that CANA regulated key proteins involved in glucose and fatty acid oxidative metabolism, including mitochondrial pyruvate carrier 1 (MPC1) and carnitine palmitoyltransferase 1B (CPT1B). Importantly, pharmacological inhibition of MPC1 or CPT1B attenuated the protective effects of CANA and aggravated cardiac structural remodeling, suggesting that these two molecules are functionally involved in CANA-mediated cardioprotection. Thus, these findings suggest that CANA ameliorates early-stage cardiac hypertrophy, at least in part, by improving myocardial energy metabolism through coordinated regulation of glucose oxidation and fatty acid oxidation pathways, highlighting its potential as an early metabolic intervention strategy for cardiac hypertrophy.

Keywords: (18)F-FDG; canagliflozin; cardiac energy metabolism; early-stage cardiac hypertrophy; micro-PET/CT

DOI: https://doi.org/10.1016/j.ejphar.2026.179176

Circulation. 2026 Jul 21. 154(3): 223-239

Loss of ATP-Dependent Citrate Lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling.

BACKGROUND: Metabolic adaptation and maladaptation are hallmarks of the failing heart and may be a target for therapeutic interventions. For example, sustained glucose oxidation during cardiac stress is associated with increased activity and abundance of ACL (ATP-dependent citrate lyase, Acly), which produces acetyl-coenzyme A (CoA) from citrate and CoA and supports de novo lipid synthesis. However, our understanding of how ACL supports cardiac metabolic adaptation and its potential to modulate disease pathophysiology has not yet been investigated.
METHODS: We used human heart tissue samples from healthy donors and patients with nonischemic cardiomyopathy. Next, we used CRISPR (clustered, regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated 9) gene editing to inactivate Acly in cardiomyocytes of Myh6-Cas9 mice. In vivo positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to Acly knockdown. We conducted a multi-omics analysis using RNA sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level.
RESULTS: We observed reduced ACL abundance and activity in human heart tissue samples from patients with nonischemic cardiomyopathy, which correlated with decreased abundance of Krebs cycle intermediates. Using CRISPR/Cas9 gene editing, we found that cardiac-specific loss of ACL reduces acetyl-CoA synthesis, leading to altered cardiac metabolism characterized by increased glucose uptake and oxidation, impaired energy flux, and elevated AMP to ATP ratios, which collectively promote left ventricular dysfunction. Transcriptomic and mass spectrometry-based metabolomics, as well as proteomic data, reveal compensatory cardiac lipid remodeling and reduced histone 3 acetylation. This metabolic stress promotes activation of AMPK (AMP kinase) and PKA (protein kinase A), which in turn mediates YAP (Yes-associated protein) inhibition through phosphorylation. Stable isotope tracer studies combined with CardioNet simulations demonstrated that increased IDH1 (isocitrate dehydrogenase 1) activity prevents allosteric inhibition of glycolysis from cytosolic citrate accumulation. AAV9-mediated cardiac Idh1 deletion improved cardiac function and energy provision, reducing YAP phosphorylation and restoring downstream YAP signaling.
CONCLUSIONS: Our findings suggest that ACL plays a pivotal role in cardiac metabolism through regulating lipid synthesis and cardiac function. Exploiting compensatory pathways of citrate metabolism may improve cardiac function during heart failure.

Keywords: ATP-dependent citrate lyase; cardio-oncology; metabolism; systems biology

DOI: https://doi.org/10.1161/CIRCULATIONAHA.125.076453

Circulation. 2026 Jul 21. 154(3): 240-242

Cracking the Code of Cardiac ATP-Dependent Citrate Lyase With Wet and Dry Tools.

Matthew A Walker, Rong Tian.

Keywords: ATP citrate (pro-S)-lyase; Editorials; metabolism; systems biology

DOI: https://doi.org/10.1161/CIRCULATIONAHA.126.081162

Cardiovasc Res. 2026 Jul 24. pii: cvag152. [Epub ahead of print]

CKD disrupts cardiac energy metabolism and aggravates cardiac inflammation, oxidative stress, and dysfunction post-infarction.

AIMS: Patients with chronic kidney disease (CKD) display a reduced survival following myocardial infarction (MI). As the underlying mechanisms remain unclear, we examined the impact of CKD on cardiac remodeling and function post-MI using a mouse model of adenine-induced CKD.
METHODS AND RESULTS: After MI, CKD mice showed a stronger cardiac dysfunction compared to non-CKD controls. While immunohistochemical and immunofluorescence analyses did not reveal changes in cardiomyocyte apoptosis, infarction size, or myofibroblast content, CKD mice exhibited an increased number of circulating myeloid cells post-infarction and more neutrophil infiltration in the heart. Combining RNAseq, untargeted kinome profiling, western blotting, and mass spectrometry revealed that post-MI, CKD enhanced cardiac oxidative stress and the acute stress complex S100A8/A9 in circulation and the heart, and enforced cardiac MAP-kinase p38 activation and NR4A1 phosphorylation as pathways underlying cardiomyocyte dysfunction. S100A8/A9 also exerted an acute detrimental impact on calcium flux and sarcomere shortening in cardiomyocytes ex vivo. Increased myeloid cell-derived S100A8/A9 expression was confirmed in the infarcted human heart by single-nucleus RNAseq, and CKD patients had higher post-infarction S100A8/A9 levels compared to patients without kidney dysfunction. Furthermore, integrating metabolomics, RNAseq, and mitochondrial analysis uncovered a disturbed cardiac metabolism with impaired glycolysis, a reduced glycerol-3-phosphate-shuttle, and a reduced Coenzyme A-bioavailability in CKD vs. non-CKD mice post-MI. These alterations were associated with poorer cardiac performance post-MI, without intrinsic defects in mitochondrial function observed.
CONCLUSION: Our study reveals innate immune activation, inflammation, oxidative stress, and metabolic alterations indicative of reduced glycolytic entry and CoA bioavailability along with aggravated cardiac dysfunction post-MI in CKD compared to non-CKD conditions, independent of infarct size, and with poorer cardiac performance in CKD associated with the cardiac metabolic alterations. Combined, this could contribute to the worsened outcome of CKD patients post-MI and reveals cardiac metabolism in CKD as an interesting translational research target.

Keywords: Cardiomyocytes; Cardiovascular disease; Chronic kidney disease; Glycolysis; Inflammation; Innate immunity; Metabolism; Myocardial infarction

DOI: https://doi.org/10.1093/cvr/cvag152