bims-hafaim 2025-01-12 papers

Issue of 2025–01–12
four papers selected by
Kyle McCommis, Saint Louis University

Physiol Rep. 2024 Sep;12(18): e70072

Hypertension and obesity independently drive hypertrophy and alter mitochondrial metabolism in a mouse model of heart failure with preserved ejection fraction.

Benjamin Werbner, Sophie L Stephens, Deborah Stuart, Travis M Hotchkiss, Jonathan Chapman, Katsuhiko Funai, Nirupama Ramkumar, Sihem Boudina.

Heart failure with preserved ejection fraction (HFpEF) has recently emerged as an insidiously and increasingly prevalent heart failure phenotype. HFpEF often occurs in the context of hypertension and obesity and presents with diastolic dysfunction, ventricular hypertrophy, and myocardial fibrosis. Despite growing study of HFpEF, the causal links between early metabolic changes, bioenergetic perturbations, and cardiac structural remodeling remain unclear. This study sought to elucidate the contribution of the respective pathophysiological drivers of the HFpEF symptom suite using a recently developed two-hit mouse model. By studying the independent and concomitant consequences of hypertension and obesity-driven metabolic dysfunction on cardiac structure and function, we revealed the causative drivers of cardiac functional, structural, and metabolic remodeling in male HFpEF mice. We found that hypertensive male mice developed diastolic dysfunction and cardiac hypertrophy regardless of obesity status and that obese mice exhibited altered systemic glucose metabolism and increased cardiac mitochondrial fatty-acid metabolism independent of hypertension status. Taken together, our results suggest that the cardiac structural and metabolic HFpEF symptoms in this two-hit model occur as direct results of each of the two "hits." The results of this study help to clarify the pathogenic HFpEF cascade, providing causal insights that may aid in the development of more precisely targeted therapeutics.

Keywords: HFpEF; cardiac hypertrophy; chronic hypertension; fatty‐acid oxidation; obesity

DOI: https://doi.org/10.14814/phy2.70072

Sheng Li Xue Bao. 2024 Dec 25. 76(6): 865-880

[Cardiac β-adrenergic receptor regulation of mitochondrial function in heart failure].

Ai-Ming Liu, Wen-Li Xu, Han Xiao, Er-Dan Dong.

Heart failure is characterized by abnormal β-adrenergic receptor (β-AR) activation and mitochondrial dysfunction. In heart failure, overactivation of β-AR mediates key pathological processes in cardiomyocytes, including oxidative stress, calcium overload and metabolic abnormalities, which subsequently lead to inflammation, myocardial apoptosis and necrosis. Mitochondria are the core organelles for energy metabolism, and also play a vital role in calcium homeostasis, redox balance and signaling transduction. Moderate β-AR activation is conducive to maintaining mitochondrial homeostasis and physiological cardiomyocyte function. However, β-AR overactivation in heart failure disrupts mitochondrial function through multiple mechanisms. Therefore, our review aims to elucidate how β-AR regulates mitochondrial function, particularly under sympathetic stress, impacting oxidative stress, apoptosis, necrosis, and metabolic imbalance. By describing these mechanisms, we seek to propose new insights and therapeutic targets for the prevention and treatment of heart failure.

Int J Biol Sci. 2025 ;21(2): 725-744

Mitochondrial SIRT2-mediated CPT2 deacetylation prevents diabetic cardiomyopathy by impeding cardiac fatty acid oxidation.

Yaoyao Guo, Ziyin Zhang, Zheng Wen, Xiaonan Kang, Dan Wang, Lu Zhang, Mengke Cheng, Gang Yuan, Huihui Ren.

Dysregulated energy metabolism, particularly lipid metabolism disorders, has been identified as a key factor in the development of diabetic cardiomyopathy (DCM). Sirtuin 2 (SIRT2) is a deacetylase involved in the regulation of metabolism and cellular energy homeostasis, yet its role in the progression of DCM remains unclear. We observed significantly reduced SIRT2 expression in DCM model mice. Cardiac-specific overexpression of SIRT2 protected mice from streptozotocin/high-fat diet (STZ/HFD)-induced insulin resistance (IR), cell apoptosis, and cardiac dysfunction, whereas its downregulation exacerbated these conditions. Moreover, we found that SIRT2 regulated cardiac lipid accumulation and fatty acid oxidation (FAO), and identified its localization in cardiac mitochondria. Mechanistically, we determined carnitine palmitoyltransferase 2 (CPT2) as a critical substrate of SIRT2, which is implicated in DCM. SIRT2-mediated deacetylation at K239 enhanced CPT2 ubiquitination, resulting in decreased protein stability and subsequent inhibition of FAO and reactive oxygen species (ROS) production. Taken together, these findings suggest that the SIRT2/CPT2 signaling pathway plays a crucial role in DCM progression.

Keywords: CPT2; SIRT2; deacetylation; diabetic cardiomyopathy; fatty acid oxidation

DOI: https://doi.org/10.7150/ijbs.102834

Cell Mol Life Sci. 2025 Jan 08. 82(1): 39

The protective effects of liraglutide in reducing lipid droplets accumulation and myocardial fibrosis in diabetic cardiomyopathy.

Chien-Yin Kuo, Sing-Hua Tsou, Edy Kornelius, Kuei-Chuan Chan, Kai-Wei Chang, Jung-Chi Li, Chien-Ning Huang, Chih-Li Lin.

BACKGROUND: Diabetes is a primary contributor to diabetic cardiomyopathy (DbCM), which is marked by metabolic imbalances such as elevated blood glucose and lipid levels, leading to significant structural and functional alterations in the myocardium. Elevated free fatty acids (FFAs) and hyperglycemia play critical roles in DbCM development, with FFAs inducing insulin resistance in cardiomyocytes and promoting lipid accumulation, resulting in oxidative stress and fibrosis. Current research suggests that glucagon-like peptide-1 (GLP-1) receptor agonists may effectively mitigate DbCM, although an effective treatment for this condition remains elusive, and the precise mechanisms of this protective effect are not fully understood.
METHODS: In this study, we aimed to replicate diabetic glucolipotoxic conditions by treating differentiated H9c2 cells with high glucose and free fatty acids. Additionally, a diabetic cardiomyopathy model was induced in mice through high-fat diets. Both in vitro and in vivo models were used to investigate the protective effects of liraglutide on cardiomyocytes and elucidate its underlying molecular mechanisms.
RESULTS: Our findings indicate that liraglutide significantly reduces lipid droplet (LD) formation and myocardial fibrosis, as evidenced by decreased expression of fibrosis markers, including TGF-β1 and collagen types I and III. Liraglutide also enhanced AMP-activated protein kinase (AMPK) activation, which improved mitochondrial function, increased antioxidant gene expression, enhanced insulin signaling, and reduced oxidative stress.
CONCLUSIONS: These results demonstrate the potential therapeutic role of liraglutide in managing diabetes-related cardiac complications, offering a comprehensive approach to improving cardiac outcomes in patients with diabetes.

Keywords: AMP-activated protein kinase (AMPK); Diabetic cardiomyopathy; Fibrosis; Lipid droplet; Liraglutide

DOI: https://doi.org/10.1007/s00018-024-05558-9