O-GlcNAcylation is a ubiquitous post-translational modification regulated by O-GlcNAcase (OGA) and O-GlcNAc transferase (OGT) in response to environmental and genetic alterations. It occurs in the nucleus, mitochondrion, and cytoplasm and is implicated in cardiovascular disease (CVD) development. O-GlcNAcylation modulates diverse cellular processes, including metabolic pathways, signaling networks, and transcriptional programs. Acute increase in O-GlcNAcylation serves as an adaptive response that preserves cardiac function, whereas chronic elevation leads to persistent metabolic dysregulation and promotes pathological cardiac remodeling. In this review, we provide a comprehensive overview of the role of O-GlcNAcylation across diverse disease contexts. We also summarize the current understanding of its complex interplay with CVD, including the underlying mechanisms. Finally, we highlight existing knowledge gaps and discuss the therapeutic potential of targeting O-GlcNAcylation in various cardiovascular events, emphasizing key priorities for future research.

Two-pore domain potassium (K₂P) channels are the most recently identified family of potassium channels. They are regarded as the largest group of background “leak” channels, encoded by 15 mammalian KCNK genes, and divided into six subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). These channels have a role in stabilizing the resting membrane potential. Their widespread presence in the heart and vasculature supports cellular homeostasis by regulating cardiac rhythm, vascular tone, and protection against ischemic stress. The TASK, TWIK, and TREK subfamilies are the most abundantly expressed K₂P channel subfamilies in the cardiovascular system, and dysregulation of specific members has been strongly linked to the development of major cardiovascular diseases. Mutations in TASK-1 have been identified in patients with pulmonary arterial hypertension, providing human genetic evidence linking K₂P dysfunction to pulmonary vascular disease. While alterations in other K₂P channels, such as TREK-1, have been demonstrated in preclinical studies where reduced channel activity is associated with ischemia–reperfusion injury and promotes cardiac arrhythmias. Growing evidence suggests that K₂P channels could serve as promising therapeutic targets, with pharmacological activation of TASK-1 and TREK-1, for instance, that might help restore vascular tone, reduce remodeling, and offer cardioprotection. Their unique leak-channel properties enable the development of highly selective treatments. This review addresses the molecular biology, physiological roles, and disease relevance of K₂P channels in the cardiovascular and pulmonary systems, emphasizing their potential as targets for innovative therapies in cardiovascular diseases.

Introduction: Animal models of cardiac dysfunction and heart failure play important roles in preclinical study and drug discovery. Cardiovascular disease and metabolic dysfunction-associated steatohepatitis (MASH) are closely associated metabolic disorders that frequently coexist in individuals with obesity and metabolic syndrome. However, the mechanisms linking diet-induced metabolic stress to cardiac dysfunction and hepatic pathology remain understudied. Method: In this study, six-week-old C57Bl/6J male mice were fed standard normal chow or a Gubra Amylin NASH (GAN) diet for six months to investigate the concurrent cardiac and hepatic manifestations. Results: Our results indicated that GAN diet-fed mice developed early cardiac dysfunction characterized by reduced ejection fraction (EF) and impaired diastolic function, as indicated by increased E/A and E/E′ ratios. These cardiac changes were accompanied by worsening hepatic pathology, including elevated total cholesterol (TC) and liver injury markers such as ALT, AST and ALP. By 6 months, mice developed pronounced fibrotic remodeling and inflammation in both the heart and liver, as confirmed by histopathological and gene expression analyses. Metabolic assessments further demonstrated a decreased respiratory exchange ratio (RER) in GAN diet-fed mice, particularly during the dark cycle, suggesting enhanced lipid utilization and decreased metabolic flexibility. In addition, reduced oxygen consumption, carbon dioxide production, and locomotor activity suggested impaired energy expenditure and reduced physical activity levels. Conclusion: Collectively, our findings demonstrate that chronic GAN diet feeding induces early cardiac dysfunction accompanied by progressive MASH-like hepatic pathology, with inflammation and fibrotic remodeling developing in both the heart and liver. These findings establish GAN diet feeding as a useful model for investigating the concurrent cardiac and hepatic consequences of chronic metabolic stress.