bims-hafaim 2025-08-10 papers

Issue of 2025–08–10
four papers selected by
Kyle McCommis, Saint Louis University

EMBO Mol Med. 2025 Aug 04.

Left ventricular myocardial molecular profile of human diabetic ischaemic cardiomyopathy.

Benjamin Hunter, Yunwei Zhang, Dylan Harney, Holly McEwen, Yen Chin Koay, Michael Pan, Cassandra Malecki, Jasmine Khor, Robert D Hume, Giovanni Guglielmi, Alicia Walker, Shashwati Dutta, Vijay Rajagopal, Anthony Don, Mark Larance, John F O'Sullivan, Jean Y H Yang, Sean Lal.

Ischaemic cardiomyopathy is the most common cause of heart failure and often coexists with diabetes mellitus, which worsens patient symptom burden and outcomes. Yet, their combined effects are seldom investigated and are poorly understood. To uncover the influencing molecular signature defining ischaemic cardiomyopathy with diabetes, we performed multi-omic analyses of ischaemic and non-ischaemic cardiomyopathy with and without diabetes against healthy age-matched donors. Tissue was sourced from pre-mortem human left ventricular myocardium. Fatty acid transport and oxidation proteins were most downregulated in ischaemic cardiomyopathy with diabetes relative to donors. However, the downregulation of acylcarnitines, perilipin, and ketone body, amino acid, and glucose metabolising proteins indicated lipid metabolism may not be entirely impaired. Oxidative phosphorylation, oxidative stress, myofibrosis, and cardiomyocyte cytoarchitecture also appeared exacerbated principally in ischaemic cardiomyopathy with diabetes. These findings indicate that diabetes confounds the pathological phenotype in heart failure, and the need for a paradigm shift regarding lipid metabolism.

Keywords: Confocal Microscopy; Diabetes; Human Myocardium; Ischaemic Cardiomyopathy; Multi-omics

DOI: https://doi.org/10.1038/s44321-025-00281-9

J Am Heart Assoc. 2025 Aug 06. e040093

Sodium Glucose Transporter 2 Inhibitor Protects Against Heart Failure With Preserved Ejection Fraction: Preclinical "2-Hit" Model Reveals Autophagy Enhancement Via AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Complex 1 Pathway.

Xinyu Hu, Dan Li, Weijie Chen, Hongyu Kuang, Dan Yang, Zhiyan Gong, Yuxiang Long, Guangliang Liu, Kai Wang, Mengshi Xia, Yanping Xu, Yuehui Yin.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a multifaceted syndrome with high morbidity and mortality. Empagliflozin, an SGLT2 (sodium-glucose cotransporter 2) inhibitor, reduces adverse events in patients with HFpEF regardless of glycemic control. However, the precise cardioprotective mechanisms of SGLT2 inhibitor in HFpEF remain underexplored.
METHODS AND RESULTS: A "2-hit" mouse model of HFpEF was developed via the high-fat diet combined with Nω-nitro-L-arginine methyl ester. Male C57BL/6N mice were assigned to either a control group (n=10) or an HFpEF group (n=20), with the latter receiving empagliflozin (10 mg/kg per day, n=10) or vehicle (n=10) for 8 weeks. Cardiac function, hypertrophy, and fibrosis were evaluated by physiological, biochemical, and histological measurements. Mechanistic analysis, including RNA sequencing, Western blotting, and immunohistochemistry, was conducted. In vitro, H9c2 cardiomyocytes were exposed to angiotensin II and palmitate, followed by empagliflozin treatment. In vivo, empagliflozin treatment improved body weight, blood pressure, glucose tolerance, and reduced cardiac hypertrophy, fibrosis, and diastolic dysfunction in HFpEF mice. Mechanistic analysis revealed that empagliflozin modulated the AMPK (AMP-activated protein kinase)/mTORC1 (mammalian target of rapamycin complex 1)/autophagy signaling pathway. Specifically, empagliflozin restored the autophagy markers (Beclin1 and LC3-II [microtubule-associated protein 1 light chain 3]) and altered the phosphorylation of AMPK, mTOR, and p70S6K (ribosomal protein S6 kinase beta-1). Inhibition of AMPK or autophagy nullified the antihypertrophic effect of empagliflozin, underscoring the dependence on the AMPK/mTORC1/autophagy pathway.
CONCLUSIONS: Empagliflozin effectively ameliorates cardiac remodeling and diastolic dysfunction in HFpEF by enhancing autophagy via the AMPK/mTORC1 pathway. These findings elucidate the direct cardioprotective mechanisms of empagliflozin and suggest potential therapeutic molecular targets for HFpEF.

Keywords: HFpEF; SGLT2 inhibitor; autophagy; cardiac remodeling; diastolic function

DOI: https://doi.org/10.1161/JAHA.124.040093

Sci Data. 2025 Aug 02. 12(1): 1347

The cardiac phospho-proteome during pressure overload in mice.

Rhys Wardman, Steve Grein, Jennifer Schwartz, Frank Stein, Joerg Heineke.

Transaortic constriction (TAC) is a murine model of pressure overload-induced cardiac hypertrophy and heart failure. Despite its high prevalence during aortic stenosis or chronic arterial hypertension, the global alterations in cardiac phospho-proteome dynamics following TAC remain incompletely characterised. We present a database of the phospho-proteomic signature one day and seven days after TAC. Utilising proteomic and phospho-proteomic analyses, we quantified thousands of proteins and phosphorylation sites, revealing hundreds of differential phosphorylation events significantly altered in the cardiac response to pressure overload. Our analysis highlights significant changes in hypertrophic signalling, metabolic remodelling, contractile function, and the stress response pathways. We present proteomic data from the main cardiac cell types (endothelial cells, fibroblasts and cardiomyocytes) to reveal the cellular localisation of the detected phospho-proteins, offering insights into temporal and site-specific phosphorylation events, facilitating the potential discovery of novel therapeutic targets and biomarkers. By making this resource publicly available (ProteomeXchange with identifier PXD061784) we aim to enable further exploration of the molecular basis of cardiac remodelling and advance translational research in heart failure.

DOI: https://doi.org/10.1038/s41597-025-05506-7

J Transl Med. 2025 Aug 06. 23(1): 870

CD36 attenuates pressure overload-induced myocardial insulin resistance via HSF1-dependent HSP90α suppression and competitive disruption of the HSP90α-InsR complex.

Hongyang Shu, Na Li, Qinqing Zhao, Zixuan Zhang, Yating Qin, Jiali Nie, Dao Wen Wang, Ning Zhou.

BACKGROUND: Insulin resistance (IR) is an early hallmark of pressure overload-induced myocardial injury and heart failure. Although CD36, a fatty acid transporter, regulates systemic insulin sensitivity, its role in myocardial insulin resistance under pressure overload remains unclear. This study aimed to elucidate CD36's cardioprotective mechanisms in this context.
METHODS: Myocardial tissues from dilated cardiomyopathy patients, transverse aortic constriction (TAC) mice, and cultured hypertrophic cardiomyocytes were analyzed for CD36 expression and insulin sensitivity. CD36 overexpression was induced via rAAV9-tnt-CD36. InsR-interacting proteins in CD36-overexpressing cells were profiled using tandem mass spectrometry, identifying HSP90α as the key partner. HSP90α agonists were used in rescue experiments. Glucose uptake (2-NBDG assay) and InsR/Akt phosphorylation were measured. Mechanistic studies included immunofluorescence, subcellular fractionation, and HSF1 transcriptional regulation analysis.
RESULTS: CD36 levels and insulin sensitivity were reduced in dilated cardiomyopathy patients, TAC mice, and hypertrophic cardiomyocytes. CD36 overexpression enhanced glucose uptake and insulin signaling. Mass spectrometry identified HSP90α (not HSP90β) as the critical InsR partner modulated by CD36. HSP90α agonists reversed CD36-mediated improvements in glucose uptake and InsR/Akt phosphorylation. Mechanistically, CD36 disrupted HSP90α-InsR binding via (1) HSF1-dependent transcriptional suppression of HSP90α and (2) competitive displacement of HSP90α from InsR. Pathological conditions increased cytosolic InsR-HSP90α trapping, while CD36 redistributed InsR to the plasma membrane.
CONCLUSION: CD36 mitigates pressure overload-induced insulin resistance by dual mechanisms: suppressing HSP90α expression via HSF1 inhibition and competitively displacing HSP90α to promote InsR membrane localization. This stabilizes insulin signaling and restores metabolic homeostasis, highlighting CD36 as a therapeutic target for heart failure involving metabolic-cardiac crosstalk.

DOI: https://doi.org/10.1186/s12967-025-06926-0