RT Journal Article
SR Electronic
T1 <strong>Specific Lowering of ADMA by Pharmacological DDAH Improves Endothelial Function, Reduces Blood Pressure and Ischemia-Reperfusion Injury</strong>
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP JPET-AR-2020-000212
DO 10.1124/jpet.120.000212
A1 Lee, Young
A1 Mehrotra, Purvi
A1 Basile, David
A1 Ullah, MD Mahbub
A1 Singh, Arshnoor
A1 Skill, Nicholas
A1 Younes, Subhi Talal
A1 Sasser, Jennifer
A1 Shekhar, Anantha
A1 Singh, Jaipal
YR 2020
UL http://jpet.aspetjournals.org/content/early/2020/11/19/jpet.120.000212.abstract
AB Multiple clinical and preclinical studies have demonstrated that plasma levels of asymmetric dimethylarginine (ADMA) are strongly associated with hypertension, diabetes, cardiovascular and renal disease. Genetic studies in rodents have provided evidence that ADMA metabolizing dimethylarginine dimethylaminohydrolase(DDAH-1) plays a role in hypertension and cardiovascular disease. However, it remains to be established whether ADMA is a bystander, biomarker or sufficiently contributes to the pathogenesis of hypertension, and cardiovascular and renal disease. The goal of the present investigation was to develop a pharmacological molecule to specifically lower ADMA and determine the physiological consequences of ADMA lowering in animal models. Further, we sought to determine if ADMA lowering will produce therapeutic benefits in vascular disease in which high ADMA levels are produced. A novel long acting recombinant DDAH (M-DDAH) was produced by post-translational modification which effectively lowered ADMA in vitro and in vivo. Treatment with M-DDAH improved endothelial function as measured by increase in cGMP and in vitro angiogenesis. In a rat model of hypertension, M-DDAH significantly reduced blood pressure (vehicle: 187{plus minus}19 mmHg vs M-DDAH: 157{plus minus}23 mmHg; p&lt;0.05). Similarly, in a rat model of ischemia-reperfusion injury, M-DDAH significantly improved renal function as measured by reduction in serum creatinine (vehicle: 3.14{plus minus}0.74 mg/dL vs M-DDAH: 1.1{plus minus}0.75 mg/dL; p&lt;0.01), inflammation and injured tubules (vehicle: 73.1{plus minus}11.1% vs M-DDAH: 22.1{plus minus}18.4%; p&lt;0.001). These pharmacological studies have provided direct evidence for a pathological role of ADMA and the therapeutic benefits of ADMA lowering in preclinical models of endothelial dysfunction, hypertension and ischemia-reperfusion injury. Significance Statement High levels of ADMA occur in patients with cardiovascular and renal disease. A novel M-DDAH effectively lowers ADMA, improves endothelial function, reduces blood pressure and protects from ischemia-reperfusion renal injury.