Endothelin and the Cardiovascular System: The Long Journey and Where We Are Going.

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.

ChGn-2 Plays a Cardioprotective Role in Heart Failure Caused by Acute Pressure Overload.

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.

Reduction of Serum Uric Acid Associated with Attenuation of Renal Injury, Inflammation and Macrophages M1/M2 Ratio in Hyperuricemic Mice Model.

BACKGROUND: Hyperuricemia contributed to endothelial dysfunction, activation of the RAS system, increased oxidative stress and maladaptive immune system response. M1 and M2 macrophages were known to contribute to the onset of renal fibrosis. This study aimed to look at the effect of lowering serum uric acid levels on renal injury in mice. METHODS: This study used 25 male mice, 3 months old, that divided into 5 groups. We injected uric acid intraperitoneally, 125mg/kg/day for 7 days (UA7) and 14 days (UA14), to induce hyperuricemia and then gave allopurinol 50mg/kg/day for 7 days to lower serum uric acid levels (UA7AL7 and UA14AL7). At the end of the treatment, we measured serum uric acid levels, Glomerular Injury Score (GIS) and Arteriolar Injury Score (AIS) with PAS staining, eNOS and MCP-1 expression with Reverse Transcriptase-PCR (RT-PCR), macrophages M1/M2 ratio with anti-CD68 and anti-arginase I immunohistochemical staining. Data were analyzed by one-way ANOVA and Kruskal-Wallis test. RESULTS: Uric acid injection increased serum uric acid levels in UA7 and UA14 group (p<0.05), followed by the increase in GIS and AIS. RT-PCR showed increased expression of MCP-1 and decreased expression of eNOS. M1 macrophages count was higher than control in UA7 and UA14 whereas M2 macrophages did not show any increased count, so the ratio of macrophages M1 / M2 is higher. Decrease in serum uric acid levels reduced GIS, AIS, MCP-1 expression and macrophages M1/M2 ratio (p<0.05). CONCLUSION: Reduction of serum uric acid levels significantly reduced renal injury that occurred in mice model of hyperuricemia.