bims-lypmec 2025-06-01 papers

Int J Mol Sci. 2025 May 09. pii: 4548. [Epub ahead of print]26(10):

Molecular Mechanisms of Type 2 Diabetes-Related Heart Disease and Therapeutic Insights.

German Camilo Giraldo-Gonzalez, Alejandro Roman-Gonzalez, Felipe Cañas, Andres Garcia.

Type 2 diabetes is a significant risk factor for cardiovascular disease, particularly coronary heart disease, heart failure, and diabetic cardiomyopathy. Diabetic cardiomyopathy, characterized by heart dysfunction in the absence of coronary artery disease or hypertension, is triggered by various mechanisms, including hyperinsulinemia, insulin resistance, and inflammation. At the cellular level, increased insulin resistance leads to an imbalance in lipid and glucose metabolism, causing oxidative stress, mitochondrial dysfunction, and excess production of reactive oxygen species (ROS). This disrupts normal heart function, leading to fibrosis, hypertrophy, and cardiac remodeling. In diabetic patients, the excessive accumulation of fatty acids, advanced glycation end products (AGEs), and other metabolic disturbances further contribute to endothelial dysfunction and inflammatory responses. This inflammatory environment promotes structural damage, apoptosis, and calcium-handling abnormalities, resulting in heart failure. Additionally, diabetes increases the risk of arrhythmias, such as atrial fibrillation, which worsens cardiac outcomes. New insights into these molecular mechanisms have led to improvements in diabetes management, focusing on mitigating complications and understanding the cellular processes involved. Recent therapeutic advances, such as SGLT-2 inhibitors, have shown promise in addressing the energy imbalance and cardiac dysfunction seen in diabetic cardiomyopathy, offering new hope for better cardiovascular outcomes.

Keywords: cardiovascular; diabetes; heart; molecular

DOI: https://doi.org/10.3390/ijms26104548

Biomedicines. 2025 Apr 27. pii: 1053. [Epub ahead of print]13(5):

Lysosomal Stress in Cardiovascular Diseases: Therapeutic Potential of Cardiovascular Drugs and Future Directions.

Toshiki Otoda, Ken-Ichi Aihara, Tadateru Takayama.

Lysosomal dysfunction has emerged as a central contributor to the pathogenesis of cardiovascular diseases (CVDs), particularly due to its involvement in chronic inflammation, lipid dysregulation, and oxidative stress. This review highlights the multifaceted roles of lysosomes in CVD pathophysiology, focusing on key mechanisms such as NLRP3 inflammasome activation, TFEB-mediated autophagy regulation, ferroptosis, and the role of apolipoprotein M (ApoM) in preserving lysosomal integrity. Additionally, we discuss how impaired lysosomal acidification, mediated by V-ATPase, contributes to lipid-induced cardiac dysfunction. Therapeutically, several pharmacological agents, such as statins, SGLT2 inhibitors, TRPML1 agonists, resveratrol, curcumin, and ferroptosis modulators (e.g., GLS1 activators and icariin), have demonstrated promise in restoring lysosomal function, enhancing autophagic flux, and reducing inflammatory and oxidative injury in both experimental models and early clinical settings. However, key challenges remain, including limitations in drug delivery systems, the absence of lysosome-specific biomarkers, and insufficient clinical validation of these strategies. Future research should prioritize the development of reliable diagnostic tools for lysosomal dysfunction, the optimization of targeted drug delivery, and large-scale clinical trials to validate therapeutic efficacy. Incorporating lysosome-modulating approaches into standard cardiovascular care may offer a new precision medicine paradigm for managing CVD progression.

Keywords: NLRP3 inflammasome; SGLT2 inhibitors; glutaminase 1; lysosomal stress; regulatory complex; senescence; statins; transcription factor EB; trehalose

DOI: https://doi.org/10.3390/biomedicines13051053

Life Sci. 2025 May 24. pii: S0024-3205(25)00396-0. [Epub ahead of print] 123761

Autophagy in cardiac pathophysiology: Navigating the complex roles and therapeutic potential in cardiac fibrosis.

Ling-Xuan Dan, Song-Ping Xie.

Cardiac fibrosis is a critical factor in cardiac structural remodeling and dysfunction, closely associated with the progression of various cardiovascular diseases (CVDs), including heart failure and myocardial infarction (MI). It is characterized by excessive extracellular matrix (ECM) deposition, which disrupts normal cardiac architecture and impairs cardiac function. Autophagy, a cellular degradation and recycling mechanism, is essential for maintaining cardiac homeostasis, mitigating stress responses, and preventing cellular damage. Recent studies have revealed a significant link between autophagy and cardiac fibrosis, suggesting that autophagic dysregulation can exacerbate fibrosis by promoting fibroblast activation and ECM accumulation. Conversely, proper autophagic activity may attenuate cardiac fibrosis by removing damaged cellular components and regulating fibrotic signaling pathways. This review examines the role of autophagy in cardiac fibrosis. It also emphasizes potential pharmacological strategies that can be used to modulate autophagic processes. These strategies may serve as therapeutic approaches for treating cardiac fibrosis, with the ultimate goal of preventing excessive fibrosis and enhancing cardiac function.

Keywords: Autophagy; Cardiac fibrosis; Cardiac pathophysiology; Heart failure

DOI: https://doi.org/10.1016/j.lfs.2025.123761

Proc Natl Acad Sci U S A. 2025 Jun 03. 122(22): e2505975122

Oxr1 and Ncoa7 regulate V-ATPase to achieve optimal pH for glycosylation within the Golgi apparatus and trans-Golgi network.

Shin-Ichiro Yoshimura, Tomoaki Sobajima, Masataka Kunii, Akihiro Harada.

Maintenance of pH within membranous organelles is crucial for cellular processes such as posttranslational modifications, ligand-receptor interactions, and proteostasis. The precise mechanisms that determine the luminal pH of each organelle are not fully understood. This study investigated the mechanisms that regulate luminal pH to ensure optimal enzymatic activity. We identified Oxr1 and its paralog Ncoa7, which regulate the vacuolar-type proton pump ATPase (V-ATPase) at the Golgi apparatus and trans-Golgi network (TGN). Oxr1 and Ncoa7 were predominantly localized at the Golgi and TGN membranes, dependent on their binding to various GTP-bound Rab proteins. In vitro experiments using purified recombinant proteins indicated that Oxr1 and Ncoa7 directly bind to the catalytic subunit of V-ATPase, inhibiting its ATP hydrolytic activity via their TLDc domains. We observed significant acidification of the Golgi/TGN lumen in Oxr1- and Ncoa7-depleted cells. Lectin blot analysis demonstrated that depletion of Oxr1 and Ncoa7 led to a defect in protein glycosylation, a major enzymatic posttranslational modification in the Golgi and TGN. Furthermore, depletion of Oxr1 and Ncoa7, along with drug-induced inhibition of glycosylation, increased lysosomal pH and sensitivity to silicon dioxide-induced membrane damage. This apparent lysosomal dysfunction suggested that, in addition to the Golgi and TGN, Oxr1 and Ncoa7 also contribute to the integrity of other organelles. Our findings indicate that Oxr1 and Ncoa7 protect the Golgi and TGN lumen from excess acidification by inhibiting V-ATPase activity and providing an optimal environment for enzymatic activity in the Golgi and TGN.

Keywords: Golgi apparatus/Trans-Golgi network; Rab; V-ATPase; congenital disorders of glycosylation; glycosylation

DOI: https://doi.org/10.1073/pnas.2505975122

J Pharmacol Exp Ther. 2025 May 08. pii: S0022-3565(25)39813-7. [Epub ahead of print]392(6): 103600

Death receptor 5 agonists mitigate cardiac pathology in a chronic isoproterenol-induced cardiac remodeling and dysfunction.

Miles A Tanner, Katrina Dougherty, Laurel A Grisanti.

Heart failure is a leading cause of death. Despite the economic and health burden, few recent therapeutic advances have been made and current therapies alleviate the symptoms, but minimally impact mortality, highlighting the need for identifying novel therapeutic targets. Death receptor 5 (DR5) has been studied extensively in cancer for its role in inducing apoptosis in transformed cells. However, DR5 is ubiquitously expressed, including in the heart, where its function is poorly understood. Clinical studies have associated DR5 and its ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), with heart failure due to multiple etiologies. Previous studies in cardiac cells and mouse models have demonstrated that DR5 promotes eccentric cardiac hypertrophy through ERK1/2-dependent mechanisms and the apoptosis of myofibroblasts. ERK1/2 signaling has been associated with prosurvival mechanisms in cardiomyocytes suggesting DR5 agonism may be a novel therapeutic approach to outcomes in heart failure. We hypothesized that activation of DR5 will be protective in heart failure. Using a chronic isoproterenol administration model, mice were administered a DR5 agonist and progression of cardiac dysfunction was monitored by echocardiography. Cardiac remodeling was assessed by histology and prohypertrophic and profibrotic marker expression. Specificity of these responses was confirmed with DR5 knockout and the involvement of ERK1/2 signaling was confirmed using pharmacological inhibitors. DR5 agonists decreased cardiac remodeling and improved contractility in response to isoproterenol, which was prevented by ERK1/2 inhibition. These findings demonstrate that activation of DR5 reduces the progression of cardiac remodeling and dysfunction and may be a novel therapeutic target for heart failure treatment. SIGNIFICANCE STATEMENT: Death receptor 5 (DR5) is expressed in cardiomyocytes where its function is poorly defined and clinically, DR5 has been associated with heart failure development and severity. Previous studies show in healthy cardiomyocytes, DR5 activates ERK1/2 signaling, causing eccentric hypertrophy, which are associated with cardioprotection during heart failure. This study investigates the therapeutic potential of targeting DR5 and demonstrates that, in a chronic isoproterenol-infusion model of cardiac dysfunction, DR5 activation reduces maladaptive cardiac remodeling and preserves function through ERK1/2-dependent mechanisms.

Keywords: Death receptor 5; ERK; Heart failure

DOI: https://doi.org/10.1016/j.jpet.2025.103600

Sci Rep. 2025 May 28. 15(1): 18718

Identification of metabolic pathways and serum biomarkers in diabetic cardiomyopathy using untargeted metabolomics.

Jialong Li, Huaming Qiu, Yanjun Wu, Li Su.

Diabetic cardiomyopathy represents a significant and irreversible chronic cardiovascular complication among diabetic patients. The condition is characterised by early diastolic dysfunction, myocardial fibrosis, cardiac hypertrophy, systolic dysfunction, and other complex pathophysiological events that ultimately lead to heart failure. Untargeted metabolomic analysis represents a powerful tool for the discovery of novel biomarkers. It can not only reveal the metabolic disorder model of diabetic cardiomyopathy, and find specific biomarkers, but also help analyse its pathogenesis and provide new clues for developing treatment strategies. Nevertheless, the precise mechanisms that give rise to diabetic cardiomyopathy remain unclear. In this study, we established a rat model of diabetic cardiomyopathy. We evaluated the model using various established methods, including fasting glucose, glycated hemoglobin, insulin resistance index, cardiac histopathology, and cardiac ultrasound. We then proceeded to identify diabetic cardiomyopathy serum biomarkers by untargeted metabolomics. The potential metabolic pathways of the multiple metabolic differentials were mainly related to amino acid metabolism and arachidonic acid metabolism. Two common metabolites, 5-OxoETE and D-Glutamine, were identified through various cross-comparisons. These two metabolites have good diagnostic ability, especially between DCM vs. CTR, DCM vs. NDCM, and NDCM vs. CTR. These findings may provide new insights into the study of DCM.

Keywords: Cardiac ultrasound; Diabetic cardiomyopathy; Diagnostic biomarkers; Ejection fraction; Untargeted metabolomics

DOI: https://doi.org/10.1038/s41598-025-98753-y