Abstract Body (Do not enter title and authors here): Background & Hypothesis: Nicotinamide adenine dinucleotide (NAD) is a critical coenzyme, essential for a variety of cellular processes. Pulmonary arterial hypertension (PAH) is associated with impaired metabolism and reduced NAD levels that contribute to its hyperproliferative state. CD38 is an ecto-enzyme that degrades NAD and produces several byproducts including cyclic ADPR. We hypothesized that CD38 mediates pathological reductions in NAD levels contributing to PAH vascular remodeling.
Methods: To test this hypothesis, we evaluated expression levels of CD38 across PAH tissues, tested its functional role in human pulmonary artery endothelial cells (PAEC) and smooth muscle cells (PASMCs), and examined the response of a global CD38 knockout mouse (CD38^-/-) in an established chronic hypoxic (10% FiO2, 4 weeks) model of pulmonary hypertension.
Results: CD38 expression was elevated in human PAECs derived from PAH cases and in rodent whole lung homogenates. Media from PAEC exposed to a CD38 inhibitor (78c) led to reduced PASMC proliferation. CD38^-/- mice exposed to chronic hypoxia exhibited attenuated PH compared to cage controls. Specifically, histological assessment of murine lungs revealed reduced PA medial thickness compared to control. CD38^-/- mice exhibited reduced right ventricular systolic pressure and a corresponding decrease in Fulton Index after hypoxic exposure. Consistent with these results, targeted metabolite measurements revealed that CD38^-/- mice exhibited elevated NAD levels in the lungs.
Discussion: These results suggest that CD38 is a novel PAH target, and its deficiency restores NAD levels in the lungs and reduces pulmonary hypertension in mice.