bims-hafaim 2025-08-31 papers

Issue of 2025–08–31
four papers selected by
Kyle McCommis, Saint Louis University

ACS Omega. 2025 Aug 19. 10(32): 36082-36097

Inhibition of Cardiac p38 Highlights the Role of the Phosphoproteome in Heart Failure Progression.

Sogol Sedighi, Ting Liu, Robert O'Meally, Robert N Cole, Brian O'Rourke, D Brian Foster.

Heart failure (HF) is a complex condition. Among altered signal transduction pathways associated with HF pathogenesis, the stress-activated p38 mitogen-activated protein kinase (Mapk) pathway has attracted attention for its role in HF progression and cardiac hypertrophy. However, the mechanisms by which p38-Mapk influences HF remain unclear. Addressing knowledge gaps may provide insight into why p38 inhibition has yielded inconsistent outcomes in clinical trials. Here, we investigate the effects of p38-Mapk inhibition via SB203580 on cardiac remodeling in a guinea pig model of HF and sudden cardiac death. Using an HF model with ascending aortic constriction and daily isoproterenol (ACi) administration, we assessed three groups: sham-operated controls, untreated ACi, and ACi treated with SB203580 (ACiSB). Cardiac function was evaluated by M-mode echocardiography. Proteome and phosphoproteome profiles were analyzed using multiplexed Tandem Mass Tag labeling and LC-MS/MS. Our findings demonstrate that SB203580 treatment protects against cardiac dysfunction in HF. Proteomic data indicate that SB203580 exerts broad protection of the cardiac phosphoproteome, inhibiting maladaptive p38-dependent phosphorylation, extending to Pka and Ampk networks, ultimately protecting the phosphorylation status of critical myofibrillar and Ca2+-handling proteins. Though SB203580 had a limited impact on widespread protein changes in HF, its biosignature revealed preserved mitochondrial energetics and reduced oxidative and inflammatory stress.

DOI: https://doi.org/10.1021/acsomega.5c03687

Biochem Biophys Res Commun. 2025 Aug 20. pii: S0006-291X(25)01233-1. [Epub ahead of print]781 152518

ACAA2 lactylation and expression mediate mitochondrial dysfunction in phenylephrine-induced cardiomyocyte hypertrophy.

Yingying Guo, Meng Zhang, Wanyi Li, Man Xu, Dan Li, Yinshan Lu, Yajie Chen, Feixue Xu, Jiahao Li, Qizhu Tang.

BACKGROUND: Pathological cardiac remodeling under chronic stress involves metabolic reprogramming, with lactylation emerging as a critical post-translational regulator of cardiac energetics. Emerging evidence reveals that lactate, beyond serving as an energy substrate, dynamically regulates cellular processes through lactylation-mediated epigenetic modifications. This study investigates ACAA2, a fatty acid β-oxidation enzyme, exploring its lactylation dynamics and metabolic implications in pressure overload-induced cardiomyopathy.
METHODS: We performed RNA sequencing on cardiac tissues from mice subjected to transverse aortic constriction (TAC) and sham-operated controls at 4 weeks post-surgery. Differentially expressed lactylation-related genes were identified, with ACAA2 selected for subsequent functional characterization. Neonatal rat ventricular myocytes (NRVMs) were stimulated with phenylephrine (PE) to induce cardiomyocyte hypertrophy. RT-PCR and Western blot analyses were performed to evaluate the expression of the interest gene during cardiac remodeling. Immunoprecipitation was used to confirm the lactylation modification of ACAA2 and detect the changes in this post-translational modification after PE stimulation. RNA interference-mediated silencing of ACAA2 was employed to investigate its functional role in PE-induced hypertrophic responses. Substrate utilization analysis was performed using ELISA-based detection kits, while mitochondrial respiratory function in NRVMs was quantitatively assessed through extracellular flux measurements with the Seahorse XFe24 Analyzer.
RESULTS: Clinical and experimental analyses revealed conserved ACAA2 downregulation in dilated cardiomyopathy patients and TAC mice, showing strong negative correlations with myocardial stress markers and positive association with cardiac function. Knockdown of ACAA2 gene exacerbated PE-induced hypertrophy in NRVMs, accompanied by global lactylation reduction. Silencing of ACAA2 led to increased accumulation of free fatty acids, decreased lactate levels, reduced ATP synthesis, and impaired mitochondrial oxidative respiration, while these changes were partially rescued by sodium lactate treatment.
CONCLUSIONS: This study suggests that changes in the expression and lactylation levels of ACAA2 may contribute to the progression of PE induced pathological myocardial hypertrophy, which may be related to mitochondrial oxidative phosphorylation dysfunction. ACAA2 may serve as a potential therapeutic target for the prevention and treatment of heart failure.

Keywords: ACAA2; Cardiomyocyte hypertrophy; Lactylation; Mitochondrial function

DOI: https://doi.org/10.1016/j.bbrc.2025.152518

Mol Metab. 2025 Aug 25. pii: S2212-8778(25)00146-2. [Epub ahead of print] 102239

KAT6A acetylation regulates AMPK function and hypertrophic remodeling in the heart.

Mariko Aoyagi Keller, Andreas Ivessa, Tong Liu, Hong Li, Peter J Romanienko, Michinari Nakamura.

Diets influence metabolism and disease susceptibility, with lysine acetyltransferases (KATs) serving as key regulators through acetyl-CoA. We have previously demonstrated that a ketogenic diet alleviates cardiac pathology, though the underlying mechanisms remain largely unknown. Here we show that KAT6A acetylation is crucial for mitochondrial function and cell growth. Proteomic analysis revealed that KAT6A is acetylated at lysine (K)816 in the hearts of mice fed a ketogenic diet under hypertension, which enhances its interaction with AMPK regulatory subunits. RNA-sequencing analysis demonstrated that the KAT6A acetylation-mimetic mutant stimulates AMPK signaling in cardiomyocytes. Moreover, the acetylation-mimetic mutant mitigated phenylephrine-induced mitochondrial dysfunction and cardiomyocyte hypertrophy via AMPK activation. However, KAT6A-K816R acetylation-resistant knock-in mice unexpectedly exhibited smaller hearts with enhanced AMPK activity, conferring protection against neurohumoral stress-induced cardiac hypertrophy and remodeling. These findings indicate that KAT6A regulates metabolism and cellular growth by interacting with and modulating AMPK activity through K816-acetylation in a cell type-specific manner.

Keywords: AMPK; KAT6A; acetylation; acetyltransferase; cardiac hypertrophy; heart failure; hypertensive cardiomyopathy; ketogenic diet; ketone body; lysine acetyltransferase 6A

DOI: https://doi.org/10.1016/j.molmet.2025.102239

JACC Basic Transl Sci. 2025 Aug 21. pii: S2452-302X(25)00297-9. [Epub ahead of print]10(9): 101345

Precision Medicine: Therapeutically Targeting Mitochondrial Alterations in Heart Failure.

Alex M Parker, Jarmon G Lees, Andrew J Murray, Anida Velagic, Shiang Y Lim, Miles J De Blasio, Rebecca H Ritchie.

A substantial component of the increasing global burden of cardiovascular disease is attributed to heart failure (HF), affecting over 64 million adults worldwide. Maladaptive mitochondrial respiratory alterations and oxidative stress are major contributors to HF development and progression, with subsequent downstream myocardial energetic impairment as a strong predictor of mortality. Current conventional therapeutic approaches, including renin-angiotensin-aldosterone system inhibition and β-adrenergic blockade, target neurohormonal aspects of HF and are effective in slowing disease progression. However, although these therapies may be associated with some improvement in myocardial energetics, they do not specifically address alterations in myocardial mitochondrial respiration or redox homeostasis. Targeting mitochondria has hence become a promising approach for more effective and tailored therapies. This review summarizes metabolic derangements that drive HF progression, with a specific focus on mitochondria. Importantly, here we address the essential knowledge gaps in the field, highlighting key translational strategies used to date, and the challenges associated with therapeutically targeting mitochondrial pathways, alongside recent developments seeking to deploy novel mitochondrial-targeted therapeutic approaches to treat HF.

Keywords: cardiomyopathy; drug discovery; myocardial metabolism; oxidative stress; pharmacotherapy; respiration

DOI: https://doi.org/10.1016/j.jacbts.2025.101345