bims-hafaim 2026-05-24 papers

Issue of 2026–05–24
six papers selected by
Kyle McCommis, Saint Louis University

Circulation. 2026 May 22.

Sam68 Exacerbates Pathologic Cardiac Hypertrophy by Suppressing Cardiomyocyte Glucose Oxidation.

Junqing An, Chaoshan Han, Ying Jiang, Jiawei Shi, Huadong Li, Chenqi Wang, Jianrong Huang, Shiyue Xu, Jie Ni, Yangpo Cao, Yuliang Feng, Qing Lv, Nianguo Dong, Gangjian Qin.

BACKGROUND: Metabolic remodeling, marked by maladaptive shifts in substrate use and energy production, is a hallmark of pathologic cardiac hypertrophy. Yet the mechanisms linking stress signaling to impaired myocardial glucose oxidation remain incompletely defined. Sam68 (Src-associated in mitosis, 68 kDa; also known as KHDRBS1 [KH domain-containing, RNA-binding, signal transduction-associated protein 1]), a STAR (signal transduction and activation of RNA) family RNA-binding protein, has not previously been implicated in cardiac metabolic control.
METHODS: Sam68 expression was examined in failing human hearts and transcriptomic data sets. Cardiomyocyte-specific Sam68 knockout mice (Sam68cKO) and AAV9 (adeno-associated virus serotype 9)-cTnT (cardiac troponin T)-mediated cardiomyocyte Sam68 overexpression (Sam68OE) were studied in transverse aortic constriction and angiotensin II models. Mechanistic studies included RNA sequencing, targeted metabolomics, in vivo [U-13C]-glucose tracing, coimmunoprecipitation, and protein-protein docking. Therapeutic relevance was tested with a PDK4 (pyruvate dehydrogenase kinase 4) inhibitor and the Sam68-Src interface blocker YB-0158, including pharmacokinetics, target engagement, and validation in Sam68cKO mice.
RESULTS: Sam68 was increased in failing human cardiomyocytes and in murine hypertrophic hearts. Sam68cKO markedly attenuated angiotensin II- and transverse aortic constriction-induced hypertrophy, whereas Sam68OE aggravated remodeling and dysfunction. In vivo [U-13C]-glucose flux analysis showed that transverse aortic constriction caused sustained uncoupling of glycolysis from glucose oxidation, with increased glycolytic labeling but reduced 13C incorporation into tricarboxylic acid cycle intermediates at 3 days and 4 weeks. Sam68 deletion restored glucose-derived carbon entry into the tricarboxylic acid cycle, enhanced PDH (pyruvate dehydrogenase)-dependent M+2 labeling, and improved oxidative-anaplerotic balance during pressure overload. Mechanistically, Sam68 served as a stress-activated scaffold that promoted Src-dependent STAT3 (signal transducer and activator of transcription 3) Tyr705 phosphorylation, nuclear accumulation, and transcriptional induction of PDK4, leading to PDH Ser293 phosphorylation and suppression of PDH activity. The PDK4 inhibitor blunted Sam68OE-driven remodeling while preserving PDH activity and mitochondrial respiratory programs. YB-0158 achieved cardiac exposure, disrupted Sam68-Src engagement in vivo, suppressed STAT3-PDK4-PDH signaling, and improved transverse aortic constriction remodeling; these effects were lost in Sam68cKO mice, supporting on-target dependence. In failing human hearts, the Src-Sam68-STAT3-PDK4 axis was activated, and Sam68 abundance increased in parallel with PDK4 and reduced left ventricular ejection fraction.
CONCLUSIONS: Sam68 is a stress-activated cardiomyocyte scaffold that drives pathologic hypertrophy through a Src-STAT3-PDK4 program that inhibits PDH and suppresses glucose oxidation. Genetic or pharmacologic disruption of this axis restores PDH-dependent pyruvate oxidation and limits pressure-overload remodeling, identifying Sam68 as a druggable metabolic control node in heart failure.

Keywords: cardiomegaly; heart failure; pyruvate dehydrogenase kinase 4; ventricular remodeling

DOI: https://doi.org/10.1161/CIRCULATIONAHA.125.077533

Circulation. 2026 May 22.

SREBP1 Transactivation of NHE3 Impairs Cardiac Contraction and Aggravates Heart Failure.

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is characterized by impaired contractility and high mortality. Dysregulation of intracellular ion (ie, Na+/H+ and Ca2+) cycling underlies reduced cardiac contractility. The mechanisms linking myocardial stress to this ion dysregulation remain incompletely understood. Although the metabolic transcription factor SREBP1 (sterol regulatory element-binding protein 1) remodels cardiac metabolism, its role in HFrEF without metabolic comorbidities, particularly regarding ion handling, remains undefined.
METHODS: Cardiac tissues from HFrEF patients and mice subjected to transverse aortic constriction (TAC) were analyzed for SREBP1 transactivation of sodium-hydrogen exchanger 3 (NHE3). Cardiomyocyte-specific SREBP1 transgenic (Srebp1a-Tg) and knockdown (Cre-Srebp1f/f) mice were generated. AAV9 vectors carrying Slc9a3 (encoding NHE3), Srebp1a or shRNA against Slc9a3, driven by the cardiomyocyte-specific cTnT promoter, were used to validate the role of the SREBP1-NHE3 in HFrEF.
RESULTS: SREBP1 was activated in human hearts with HFrEF because of dilated cardiomyopathy, but without diabetes or hyperlipidemia, and in TAC-induced HFrEF mouse hearts. Srebp1a-Tg mice exhibited impaired cardiac contractility with dysregulated calcium handling in cardiomyocytes without apparent lipid accumulation. Transcriptomics analysis identified increased NHE3 expression in Srebp1a-Tg mice, confirmed by NHE3 upregulation in TAC hearts and human failing hearts. ChIP-seq, ChIP, and promoter reporter assay demonstrated direct transcriptional regulation of Slc9a3 (encoding NHE3) by SREBP1. NHE3 activity was enhanced in cardiomyocytes isolated from Srebp1a-Tg mice or those underwent TAC, whereas cardiomyocyte-specific Srebp1 knockdown in TAC mice reduced NHE3 activity. Cardiomyocyte-specific knockdown of Srebp1 or Slc9a3 restored calcium handling and improved cardiac function in TAC mice. In Srebp1a-Tg mice, NHE3 knockdown alleviated Na+ and Ca2+ overload and rescued cardiac systolic dysfunction. Conversely, NHE3 overexpression caused contractile impairment in both Cre-Srebp1f/f mice and controls, which offset the protective effect because of SREBP1 loss in the context of Na+ and Ca2+ overload.
CONCLUSIONS: SREBP1 directly transactivates cardiac NHE3 during the progression of HFrEF, leading to dysregulated calcium handling and impaired contractility, revealing a novel, noncanonical role for SREBP1 in the pathophysiology of heart failure and offering a potential new therapeutic target.

Keywords: calcium; heart failure; myocardial contraction; sodium-hydrogen exchanger 3; sterol regulatory element-binding protein 1

DOI: https://doi.org/10.1161/CIRCULATIONAHA.126.079823

Genome Med. 2026 May 18.

Multi-omics profiling of the diabetic human heart reveals coupled dysregulation in lipid metabolism, mitophagy, and extracellular matrix remodeling.

Qiuhan Lu, Shulin Tang, Sijia Fang, Yuwen Wu, Liang Chen, Mintong Liang, Jiaqi Chen, Pengju Wen, Leigang Jin, Jianshe Yu, Feng Jiao, Yueheng Wu, Guozhi Jiang.

BACKGROUND: Diabetic cardiomyopathy (DbCM) is a major complication of type 2 diabetes whose molecular basis in human hearts remains poorly understood. This study aimed to define the multi-omics landscape of DbCM in the human myocardium.
METHODS: We performed integrated transcriptomic, 4D-DIA proteomic, and full-spectrum widely targeted metabolomic analysis on left ventricular tissues from matched Chinese cohorts: DbCM (n = 11), non-diabetic cardiomyopathy (n = 11), and healthy donors (n = 4). Key findings were validated by histological assessment and western blotting of candidate proteins. External validation was conducted using public datasets, and phenotypic support was derived from mouse models.
RESULTS: Multi-omics profiling revealed distinct, coordinated dysregulation in DbCM. Proteomics and transcriptomics profiling revealed a rewired fatty acid oxidation-mitophagy axis characterized by elevated acyl-CoA synthetase long-chain family member 1 (ACSL1) and suppressed fatty acid synthase (FASN), impaired mitochondrial quality control marked by a significant reduction in the mitophagy regulator BNIP3L, which showed a strong inverse correlation with ACSL1, and disrupted extracellular matrix homeostasis, with specific downregulation of key structural components (COL5A1, COL5A2, and fibrillin-1). Metabolomics confirmed enhanced but incomplete fatty acid oxidation, evidenced by triglyceride depletion and accumulation of acylcarnitines and lipotoxic lipids. Integrated multi-omics identified impaired BNIP3L-associated mitophagy as a potential molecular node associated with lipid metabolic dysregulation with mitochondrial dysfunction.
CONCLUSIONS: This human multi-omics study defines DbCM by the concurrent dysregulation of cardiac fuel metabolism, mitochondrial quality control, and matrix remodeling, offering novel mechanistic insights and highlighting ACSL1 and BNIP3L as potential therapeutic targets for diabetes-associated cardiac dysfunction.

Keywords: Cardiomyopathy; Diabetes; Lipid metabolism; Matrix remodeling; Mitophagy; Multi-omics

DOI: https://doi.org/10.1186/s13073-026-01668-0

Res Sq. 2026 May 05. pii: rs.3.rs-9589283. [Epub ahead of print]

TACO1 regulates mitochondrial adaptation in hypertension-induced cardiac remodeling and heart failure.

Mitochondrial dysfunction drives hypertensive heart failure and reflects impaired oxidative phosphorylation and altered organelle structure. The mechanisms linking hypertensive signaling to mitochondrial translation and architecture remain unclear. TACO1 is a mitochondrial translational activator required for cytochrome c oxidase subunit I synthesis and may regulate respiratory chain assembly. We tested whether angiotensin II type 1 receptor activation disrupts TACO1-dependent translation and drives inner membrane remodeling. Using mRen also known as (mRen2)27 hypertensive rat hearts, we assessed mitochondrial function, ultrastructure, and metabolism. AT1R activation reduced TACO1-dependent COX I translation and produced a selective deficiency in complex IV activity. This impaired oxidative phosphorylation and increased the production of reactive oxygen species. Mitochondria exhibited reduced volume, increased fragmentation, and disrupted cristae organization with lower integrity scores. Hypertensive hearts also showed reduced expression of OPA1 and MICOS components. Metabolomic profiling separated control and heart failure groups and revealed enrichment of amino acid, nucleotide, and mitochondrial energy pathways. Lipidomic analysis identified coordinated changes across lipid classes consistent with altered membrane composition. Pharmacological AT1R inhibition restored COX I translation, rescued complex IV activity, and improved cristae structure. These findings establish a mechanistic link between hypertensive signaling, mitochondrial translation, cristae organization, and metabolic remodeling in heart failure.

DOI: https://doi.org/10.21203/rs.3.rs-9589283/v1

Basic Res Cardiol. 2026 May 21.

Empagliflozin restores cardiac function in obese-diabetic HFpEF mice but further alters gene expression.

Juliana Mira Hernandez, Logan R J Bailey, Victoria R Salemme, Christopher Y Ko, Erin Y Shen, Megan Ngim, Duong T Hoang, Melissa Corea, Julie Bossuyt, Jennifer M Davis, Donald M Bers, Bence Hegyi.

Effective treatments for heart failure with preserved ejection fraction (HFpEF) are limited. Empagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, provides cardiovascular benefits for patients with HFpEF. SGLT2 expression is virtually absent in cardiomyocytes, hence the exact protective mechanism of empagliflozin is unclear. We aimed to study the effect of in vivo empagliflozin treatment on excitation-contraction coupling (ECC), electrophysiology, and gene transcription in a translational two-hit HFpEF mouse model that combines the obese-diabetic leptin receptor-deficient db/db mice with chronic aldosterone infusion (db/db + Aldo). We performed morphometry, echocardiography, cardiomyocyte electrophysiology, intracellular Ca2+ imaging, and whole-heart RNA-sequencing in empagliflozin-treated db/db + Aldo and vehicle control mice. In db/db + Aldo mice, empagliflozin (in vivo, 4 weeks) reduced the elevated plasma blood glucose (13 ± 5 mmol/L versus 23 ± 8 mmol/L) and BNP levels, prevented pulmonary congestion, and ameliorated diastolic dysfunction. However, empagliflozin did not reduce cardiac hypertrophy and obesity. In healthy control mice, empagliflozin had no functional effect. Chronic in vivo empagliflozin treatment in db/db + Aldo also normalized the changes in cardiomyocyte electrophysiology and Ca2+ handling properties measured in the absence of empagliflozin in the perfusion solution during cell experiments, indicating a true phenotypic rescue. Differentially expressed gene clusters were identified characteristic of the db/db genotype, aldosterone, and empagliflozin treatments. Interestingly, empagliflozin did not just reverse the HFpEF-altered gene expression but shifted it further away from control to a new expression profile. We conclude that chronic in vivo empagliflozin treatment restores cardiomyocyte electrophysiological and ECC properties, ameliorates diastolic function in cardiometabolic HFpEF, and induces complex gene expression changes.

Keywords: Excitation–contraction coupling; Gene transcription; HFpEF; Ion channels; Preclinical animal model; SGLT2 inhibitor

DOI: https://doi.org/10.1007/s00395-026-01184-7

Circ Res. 2026 May 19.

SBK2-Driven NDUFV1 Phosphorylation and Translocation Limits Cardiac Hypertrophy.

Yazhou Sun, Qinghua Wu, Fang Lei, Lei Luo, Long Zhang, Lixing Wang, Mingliang Tang, Zifeng Yang, Song Tian, Qiongyu Wang, Qidan Li, Peng Zhang, Xiao-Jing Zhang, Hongliang Li, Zhi-Gang She.

BACKGROUND: Heart failure remains a major global health burden, driven largely by pathological cardiac hypertrophy. Mitochondrial dysfunction, particularly impaired mitochondrial complex I activity, is central to the disease progression, yet its regulatory mechanisms are poorly understood. Cross-species transcriptomic screening and UK Biobank analyses identified SBK2 (Src homology 3 domain-binding kinase 2) as a conserved, cardiac-enriched kinase potentially linked to heart failure risk. We hypothesized that SBK2 regulates cardiac hypertrophy by modulating mitochondrial complex I function.
METHODS: Cross-species conserved genes were identified from GEO data sets, and variants within ±10 kb of SBK2, ADAMTSL2 (ADAMTS-like protein 2), LOX, and SPP1 (secreted phosphoprotein 1) were assessed for heart failure association in the UK Biobank cohort. SBK2 expression was examined in experimental models and publicly available human hypertrophic cardiomyopathy data sets, and its function was investigated through loss- and gain-of-function studies in cardiomyocytes and mice. The substrates and interacting partners of SBK2 were identified by proteomic and interactome analyses and validated by in vitro kinase assays and coimmunoprecipitation. Mitochondrial protein import and respiratory supercomplex assembly were assessed by biochemical fractionation and blue native PAGE.
RESULTS: SBK2 expression was reduced in hypertrophic hearts and primary neonatal rat ventricular myocytes. Cardiomyocyte-specific overexpression of SBK2 attenuated hypertrophy and fibrosis, improved systolic function, and suppressed maladaptive gene expression. Conversely, SBK2 knockdown exacerbated these phenotypes. Mechanistically, SBK2 directly bound and phosphorylated NDUFV1 (NADH: ubiquinone oxidoreductase core subunit V1) at serine 251. This modification enhanced the interaction between NDUFV1 and the cytosolic chaperone HSPA1A and facilitated TOM70-dependent mitochondrial import. Increased mitochondrial NDUFV1 promoted complex I activity, respiratory supercomplex assembly, oxidative phosphorylation, mitochondrial fusion, and redox homeostasis. Pharmacological inhibition of complex I or NDUFV1 silencing abolished SBK2-mediated protection. Moreover, a phospho-deficient NDUFV1 mutant (S251A) failed to rescue hypertrophic phenotypes in SBK2-deficient cardiomyocytes.
CONCLUSIONS: SBK2 is an upstream kinase that couples cytosolic signaling to mitochondrial protein import by phosphorylating NDUFV1, thereby sustaining complex I integrity and mitochondrial function to restrain pathological cardiac hypertrophy. These findings uncover a previously unrecognized SBK2-NDUFV1 signaling axis linking kinase signaling to mitochondrial proteostasis and identify a potential therapeutic target for heart failure.

Keywords: fibrosis; heart failure; homeostasis; phenotype; serine

DOI: https://doi.org/10.1161/CIRCRESAHA.126.328547