PT - JOURNAL ARTICLE AU - Lee, Young AU - Singh, Jaipal AU - Scott, Susan R AU - Ellis, Bradley AU - Zorlutuna, Pinar AU - Wang, Meijing TI - A Recombinant DDAH Based Biotherapeutics to Pharmacologically Lower ADMA, thus Improving Post Ischemic Cardiac Function and Cardiomyocyte Mitochondrial Activity AID - 10.1124/molpharm.121.000394 DP - 2022 Jan 01 TA - Molecular Pharmacology PG - MOLPHARM-AR-2021-000394 4099 - http://molpharm.aspetjournals.org/content/early/2022/01/18/molpharm.121.000394.short 4100 - http://molpharm.aspetjournals.org/content/early/2022/01/18/molpharm.121.000394.full AB - High serum levels of asymmetric dimethyl arginine (ADMA) are associated with cardiovascular disease and mortality. Pharmacological agents to specifically lower ADMA, and their potential impact on cardiovascular complications are not known. In this study, we aimed to investigate the effect of specific lowering of ADMA on myocardial response to ischemia-reperfusion injury (I/R), and direct effects on cardiomyocyte function. Effects of recombinant DDAH-1 (rDDAH-1) on I/R injury were determined using isolated mouse heart preparation. Respiration capacity and mitochondrial reactive oxygen species (ROS) generation were determined on mouse cardiomyocytes. Our results show that lowering ADMA by rDDAH-1 treatment resulted in improved recovery of cardiac function and reduction in myocardial infarct size in response to I/R injury (control 22.24{plus minus}4.60% vs rDDAH-1 15.90{plus minus}4.23%, p<0.01) to mouse heart. In mouse cardiomyocytes, rDDAH-1 treatment improved ADMA-induced dysregulation of respiration capacity and decreased mitochondrial ROS. Furthermore, in human hiPSC-derived cardiomyocytes with impaired contractility under hypoxia and high ADMA, rDDAH-1 treatment improved recovery and beating frequency (p<0.05). rDDAH-1 treatment selectively modified I/R-induced myocardial cytokine expression resulting in reduction in pro-inflammatory cytokine IL-17A (p<0.001) and increased expression of anti-inflammatory cytokines IL-10 and IL-13 (p<0.01). Further in vitro studies showed that IL-17A was the predominant and common cytokine modulated by ADMA-DDAH pathway in heart, cardiomyocytes and endothelial cells. These studies show that lowering ADMA by pharmacological treatment with rDDAH-1 reduced I/R injury, improved cardiac function, and improved cardiomyocyte bioenergetics and beating activity. These effects may be attributable to ADMA lowering in cardiomyocytes and preservation of cardiomyocyte mitochondrial function Significance Statement The pathological role of ADMA has been demonstrated by its association with cardiovascular disease and mortality. Currently, pharmacological drugs to specifically lower ADMA are not available. The present study provides the first evidence that lowering of ADMA by recombinant rDDAH-1 decreased ischemia/reperfusion injury, improved post-ischemic cardiac function, and improved cardiomyocyte bioenergetics and beating activity. Our studies suggest that lowering of ADMA by pharmacologic treatment offers opportunity to develop new therapies for the treatment of cardiovascular and renal disease.