0068 : Protective role of nucleotidases against the development of hypertension

Abstract

Hypertension is characterized by a hypertrophic remodeling of big arteries, increased tone in smallest, endothelial dysfunction and accompanied by oxidative stress, inflammation and fibrosis. Extracellular nucleotides, which are released under cellular stress, promote deleterious pathological responses (vasoconstriction, inflammation, vascular permeability) through P2 receptors activation although the contribution of purinergic signaling to cardiovascular pathologies remains to be established. Hydrolysis of these molecules is provided by nucleoside triphosphate diphosphohydrolases (NTPDases), especially NTPDase1 (CD39), highly expressed in the arterial wall. Together with ecto-5’nucleotidase (CD73), these enzymes generate vasoprotective adenosine (ADO anti inflammatory, vasodilatory). Using Apyrase (APY, soluble potato nucleotidase) treatment and CD39 deficient ( Entpd1-/- ) mice, we evaluated the potential benefit of nucleotides hydrolysis in experimental hypertension. After 12 days of AngII (1mg/kg/day) infusion, with or without APY (45U sc, 15U ip every 3 days), the increase in systolic blood pressure (SBP) and the hypertrophic aortic remodeling were significantly reduced in AngII/APY-treated mice compared to AngII-treated mice. Reversely, in Entpd1-/- mice treated with intermediate dose of AngII (0.5mg/kg/day) the increase in SBP was greater than in Entpd1+/+ mice. This was associated with exacerbated hypertrophic aortic remodeling. Interestingly, RT-qPCR revealed a decreased CD39 expression level in resistance arteries of AngII-treated mice and SHR rats, suggesting a role for the enzyme in hypertension. The role of CD39 as a regulator of arterial tone through the control of P2Y6 receptor activation is likely, although its contribution in the prevention of vascular inflammation remains to be investigated. Consequently, nucleotidases protect against high blood pressure and represent new therapeutic area in the treatment of hypertension.