bims-hafaim 2025-02-16 papers

Issue of 2025–02–16
five papers selected by
Kyle McCommis, Saint Louis University

Cardiovasc Res. 2025 Feb 10. pii: cvaf005. [Epub ahead of print]

Glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor agonist tirzepatide promotes branched chain amino acid catabolism to prevent myocardial infarction in non-diabetic mice.

Mengya Chen, Nan Zhao, Wenke Shi, Yun Xing, Shiqiang Liu, Xianxian Meng, Lanlan Li, Heng Zhang, Yanyan Meng, Saiyang Xie, Wei Deng.

AIMS: A novel dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptor agonist, tirzepatide (LY3298176, TZP), has been developed to treat Type 2 diabetes mellitus (T2DM). In ischaemic heart diseases, TZP is involved in cardiac metabolic processes. However, its efficacy and safety in treating heart failure (HF) following myocardial infarction (MI) remain uncertain.
METHODS AND RESULTS: Herein, 12 week C57BL/6J mice were subjected to MI surgery, followed by administration of TZP. The effects of TZP on cardiac function and metabolism were thoroughly assessed by physiological, histological, and cellular analyses. Downstream effectors of TZP were screened through untargeted metabolomics analysis and molecular docking. Construct a lower branched chain amino acid (BCAA) diet model to determine whether TZP's cardioprotective effect is associated with reducing BCAA levels. Our results demonstrated that TZP reduced mortality following MI, decreased the infarct area, and attenuated cardiomyocyte necrosis. Pathological evaluation of cardiac tissues demonstrated increased fibrosis repair and decreased inflammatory infiltration. Mechanistically, untargeted metabolomics analysis uncovered a positive correlation between TZP and the BCAA catabolism pathway. The molecular docking verified that TZP could bind with branched-chain keto acid dehydrogenase E1 subunit α (BCKDHA). TZP reduced BCKDHA phosphorylation at S293, enhanced BCAA catabolism, and inhibited the activation of metabolism by activating rapamycin (mTOR) signalling pathway. Furthermore, mice fed a low-BCAA diet post-MI demonstrated reduced cardiomyocyte necrosis, increased fibrosis repair, and decreased inflammatory infiltration. These cardioprotective effects were further enhanced when used synergistically with TZP.
CONCLUSION: Taken together, our findings provide new perspectives on the unrecognized role of TZP in cardiac protection. TZP enhanced BCAA catabolism and attenuated BCAA/mTOR signalling pathway in MI mice. Consequently, this study may present novel therapeutic options for patients with HF.

Keywords: BCAA catabolism; Heart failure; Myocardial infarction; Tirzepatide

DOI: https://doi.org/10.1093/cvr/cvaf005

Eur J Pharmacol. 2025 Feb 06. pii: S0014-2999(25)00108-6. [Epub ahead of print]992 177355

Sodium-glucose cotransporter 2 inhibitor empagliflozin enhances autophagy and reverses remodeling in hearts with large, old myocardial infarctions.

Susumu Endo, Hiromitsu Kanamori, Akihiro Yoshida, Genki Naruse, Shingo Komura, Shingo Minatoguchi, Takatomo Watanabe, Tomonori Kawaguchi, Yoshihisa Yamada, Atsushi Mikami, Tatsuhiko Miyazaki, Haruhiko Akiyama, Hiroyuki Okura.

Large clinical trials recently showed that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve the prognosis of heart failure patients with or without diabetes. Using a mouse model of large myocardial infarction, we investigated the therapeutic effects and underlying molecular mechanisms of the highly selective SGLT2 inhibitor empagliflozin in heart failure. Four weeks after myocardial infarction induced by left coronary artery ligation, the surviving mice were assigned to vehicle or empagliflozin groups and treated for 8 weeks. Empagliflozin did not alter body weight, blood pressure, glycohemoglobin, blood glucose or beta-hydroxybutyrate levels but significantly attenuated cardiac dysfunction and left ventricular dilatation (remodeling). Hearts from empagliflozin-treated mice showed less fibrosis, less cardiomyocyte hypertrophy, and lower myocardial ANP levels than those from vehicle-treated mice. Autophagy was augmented in cardiomyocytes from empagliflozin-treated mice, as indicated by increased myocardial microtubule-associated protein-1 LC3 (light chain 3)-II levels and LC-3-II/I ratio as well as increased levels of cathepsin D and ATP. Additionally, numerous autophagic vacuoles and lysosomes were observed, accompanied by increased AMP-activated protein kinase (AMPK) phosphorylation and suppression of mammalian target of rapamycin phosphorylation. Myocardial sodium-hydrogen antiporter (NHE)-1 expression was increased in infarcted mice, and that effect was unchanged by empagliflozin. In vitro, empagliflozin increased autophagic flux and induced an intracellular pH drop, AMPK activation and ATP production in cardiomyocytes. These effects were similar to those of the NHE-1 inhibitor cariporide, suggesting a possibility that they both act on the same pathway. Empagliflozin is a beneficial pharmacological tool that enhances autophagy to reverse remodeling in the postinfarction heart.

Keywords: AMPK; Autophagy; Heart failure; Myocardial infarction; NHE-1; Remodeling; SGLT2 inhibitor

DOI: https://doi.org/10.1016/j.ejphar.2025.177355

Am J Physiol Heart Circ Physiol. 2025 Feb 11.

Retinoic Acid Signaling & Metabolism in Heart Failure.

Lauren E Parker, Kyriakos N Papanicolaou, Stephanie Zalesak-Kravec, Eva M Weinberger, Maureen A Kane, D Brian Foster.

Nearly 70 years after studies first showed that the offspring of vitamin A (retinol, ROL) -deficient rats exhibit structural cardiac defects and over 20 years since the role of vitamin A's potent bioactive metabolite hormone, all-trans retinoic acid (ATRA), was elucidated in embryonic cardiac development, the role of the Vitamin A metabolites, or retinoids, in adult heart physiology as well as heart and vascular disease, remains poorly understood. Studies have shown that low serum levels of retinoic acid correlate with higher all-cause and cardiovascular mortality, though the relationship between circulating retinol and ATRA levels, cardiac tissue ATRA levels, and intracellular cardiac ATRA signaling in the context of heart and vascular disease has only begun to be addressed. We have recently shown that patients with idiopathic dilated cardiomyopathy show a nearly 40% decline of in situ cardiac ATRA levels, despite adequate local stores of retinol. Moreover, we and others have shown that the administration of ATRA forestalls the development of heart failure (HF) in rodent models. In this review, we summarize key facets of retinoid metabolism and signaling and discuss mechanisms by which impaired ATRA signaling contributes to several HF hallmarks including hypertrophy, contractile dysfunction, poor calcium handling, redox imbalance, and fibrosis. We highlight unresolved issues in cardiac ATRA metabolism whose pursuit will help refine therapeutic strategies aimed at restoring ATRA homeostasis.

Keywords: heart disease; heart failure; metabolism; retinoic acid; vitamin A

DOI: https://doi.org/10.1152/ajpheart.00871.2024

Sci Rep. 2025 Feb 11. 15(1): 5051

Liraglutide combined with HIIT preserves contractile apparatus and blunts the progression of heart failure in diabetic cardiomyopathy rats.

Huan Cai, Chengye Dai, Jingqin Liu, Shuchun Chen.

Liraglutide has been shown to alleviate heart failure in patients with type 2 diabetes. High-intensity interval training (HIIT) has also been proven to improve cardiac function in diabetes. The present study explored the effects and underlying mechanisms of liraglutide and HIIT combination therapy in alleviating diabetic cardiomyopathy (DCM). A high-fat diet and low-dose streptozotocin (STZ) were utilized to induce the DCM model. Eight weeks of liraglutide injection and HIIT were used to treat DCM. Subsequently, cardiac function, serum metabolic biomarkers, serum glucagon-like peptide-1 (GLP-1), histology examination, cardiac alpha-myosin heavy chain (α-MHC), and β-MHC messenger RNA (mRNA) expression, forkhead box protein O1 (FOXO1) and muscle-specific RING finger protein 1 (MURF1) mRNA expression and colocalization, and expression of GLP-1 and GLP-1 receptor (GLP-1R) proteins were detected after the intervention. Results showed that DCM rats developed hyperglycemia with eccentric hypertrophy, fibrosis, and reduced systolic and diastolic function. All interventions significantly reversed the development of heart failure by alleviating the disruption of contractile apparatus, reversed the adult α-MHC transformed to fetal β-MHC, and reduced FOXO1 and MURF1 mRNA expression. Combination therapy had a better effect in alleviating cardiac fibrosis, reducing cardiovascular risk biomarkers, controlling eccentric hypertrophy, and improving systolic function. Combination therapy significantly reduced FOXO1 and MURF1 colocalization and improved the GLP-1R sensitivity in diabetic hearts. Overall, these findings demonstrate that combination therapy can reverse cardiac failure in diabetic rats by controlling the degradation of contractile apparatus by downregulating the cardiac atrophy gene expression and interrupting their colocalization, as well as upregulating GLP-1 signaling.

Keywords: Diabetic cardiomyopathy; Heart failure with preserved ejection fraction; High-intensity interval training; Liraglutide

DOI: https://doi.org/10.1038/s41598-025-85699-4

J Am Heart Assoc. 2025 Feb 14. e037637

Dietary Branched-Chain Amino Acids Modify Postinfarct Cardiac Remodeling and Function in the Murine Heart.

Daniel C Nguyen, Collin K Wells, Madison S Taylor, Yania Martinez-Ondaro, Richa Singhal, Kenneth R Brittian, Robert E Brainard, Joseph B Moore, Bradford G Hill.

BACKGROUND: Branched-chain amino acids (BCAAs), which are derived from the diet, are markedly elevated in cardiac tissue following myocardial infarction (MI). Nevertheless, it remains unclear whether dietary BCAA levels influence post-MI remodeling.
METHODS: To investigate the impact of dietary BCAAs on cardiac remodeling and function after MI, we fed mice a low or a high BCAA diet for 2 weeks before MI and for 4 weeks after MI. Cardiac structural and functional changes were evaluated by echocardiography, gravimetry, and histopathological analyses. Immunoblotting was used to evaluate the effects of BCAAs on isolated cardiac myofibroblast differentiation.
RESULTS: The low BCAA diet decreased circulating BCAA concentrations by >2-fold when compared with the high BCAA diet. Although neither body weights nor heart masses were different in female mice fed the custom diets, male mice fed the high BCAA diet had significantly higher body and heart masses than those on the low BCAA diet. The low BCAA diet preserved stroke volume and cardiac output after MI, whereas the high BCAA diet promoted progressive decreases in cardiac function. Although BCAAs were required for myofibroblast differentiation in vitro, cardiac fibrosis, scar collagen topography, and cardiomyocyte cross-sectional area were not different between the dietary groups; however, male mice fed the high BCAA diet had longer cardiomyocytes and higher capillary density compared with the low BCAA group.
CONCLUSIONS: A low BCAA diet mitigates eccentric cardiomyocyte remodeling and loss of cardiac function after MI in mice, with dietary effects more prominent in males.

Keywords: branched‐chain amino acids; fibrosis; heart failure; hypertrophy; myocardial infarction

DOI: https://doi.org/10.1161/JAHA.124.037637