Endothelin was first discovered more than 30 years ago as a potent vasoconstrictor. In subsequent years, three isoforms, two canonical receptors, and two converting enzymes were identified, and their basic functions were elucidated by numerous preclinical and clinical studies. Over the years, the endothelin system has been found to be critical in the pathogenesis of several cardiovascular diseases, including hypertension, pulmonary arterial hypertension, heart failure, and coronary artery disease. In this review, we summarize the current knowledge on endothelin and its role in cardiovascular diseases. Furthermore, we discuss how endothelin-targeting therapies, such as endothelin receptor antagonists, have been employed to treat cardiovascular diseases with varying degrees of success. Lastly, we provide a glimpse of what could be in store for endothelin-targeting treatment options for cardiovascular diseases in the future.

Background: Cardiac extracellular matrix is critically involved in cardiac homeostasis, and accumulation of chondroitin sulfate glycosaminoglycans (CS‐GAGs) was previously shown to exacerbate heart failure by augmenting inflammation and fibrosis at the chronic phase. However, the mechanism by which CS‐GAGs affect cardiac functions remains unclear, especially at the acute phase. Methods and Results: We explored a role of CS‐GAG in heart failure using mice with target deletion of ChGn‐2 (chondroitin sulfate N‐acetylgalactosaminyltransferase‐2) that elongates CS chains of glycosaminoglycans. Heart failure was induced by transverse aortic constriction in mice. The role of CS‐GAG derived from cardiac fibroblasts in cardiomyocyte death was analyzed. Cardiac fibroblasts were subjected to cyclic mechanical stretch that mimics increased workload in the heart. Significant CS‐GAGs accumulation was detected in the heart of wild‐type mice after transverse aortic constriction, which was substantially reduced in ChGn‐2 ^‐/‐ mice. Loss of ChGn‐2 deteriorated the cardiac dysfunction caused by pressure overload, accompanied by augmented cardiac hypertrophy and increased cardiomyocyte apoptosis. Cyclic mechanical stretch increased ChGn‐2 expression and enhanced glycosaminoglycan production in cardiac fibroblasts. Conditioned medium derived from the stretched cardiac fibroblasts showed cardioprotective effects, which was abolished by CS‐GAGs degradation. We found that CS‐GAGs elicits cardioprotective effects via dual pathway; direct pathway through interaction with CD44, and indirect pathway through binding to and activating insulin‐like growth factor‐1. Conclusions: Our data revealed the cardioprotective effects of CS‐GAGs; therefore, CS‐GAGs may play biphasic role in the development of heart failure; cardioprotective role at acute phase despite its possible unfavorable role in the advanced phase.

Multidrug‐resistant tuberculosis (MDR‐TB) is characterized by resistance to at least isoniazid and rifampicin. Linezolid is an antibiotic used for drug‐resistant Gram‐positive bacteria and is a treatment option for MDR‐TB. However, its use is associated with optic neuropathy, presenting as acute worsening and bilateral vision loss, typically within 4 months of therapy. A 47‐year‐old male with MDR‐TB relapsed during the sixth month of an individualized treatment regimen at Dr. Soetomo General Academic Hospital, Surabaya. The patient presented with weakness and anemia, receiving a regimen including levofloxacin (750 mg), linezolid (600 mg), clofazimine (100 mg), and cycloserine (500 mg). In the ninth month, the patient developed visual disturbances, initially suspected to be caused by an intracranial tumor. Despite various examinations and treatments, there was no improvement until linezolid was discontinued. The patient’s visual complaints gradually improved following the cessation of linezolid therapy. This case underscores the potential for linezolid to cause optic neuropathy during prolonged treatment for MDR‐TB. Detailed ophthalmologic examinations, including optical coherence tomography (OCT) and magnetic resonance imaging (MRI), confirmed optic neuropathy without intracranial pathology. Despite high‐dose steroid therapy, the patient’s vision improved only after 1 month since discontinuing linezolid. This highlights the importance of monitoring for ocular toxicity in patients undergoing long‐term linezolid therapy and suggests that timely intervention can prevent permanent visual impairment. The case demonstrates the reversible nature of linezolid‐induced optic neuropathy upon drug cessation and emphasizes the need for regular ophthalmologic assessments in patients receiving prolonged linezolid treatment. This report contributes to the understanding of the adverse effects of linezolid and underscores the importance of vigilant monitoring and alternative therapeutic strategies for MDR‐TB.