Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and Is a Therapeutic Target in Pulmonary Arterial Hypertension

Abstract

Background Pulmonary arterial hypertension (PAH) is a severe and progressive disease, a hallmark of which is pulmonary vascular remodeling. Nicotinamide phosphoribosyltransferase (NAMPT), is a cytozyme which regulates intracellular NAD levels and cellular redox state, regulates histone deacetylases, promotes cell proliferation and inhibits apoptosis. We hypothesized that NAMPT promotes pulmonary vascular remodeling, and that inhibition of NAMPT could attenuate pulmonary hypertension. Methods Plasma and mRNA and protein levels of NAMPT were measured in the lungs and isolated pulmonary artery endothelial cells (PAECs) from PAH patients, as well as in lungs of rodent models of pulmonary hypertension (PH). Nampt+/− mice were exposed 10% hypoxia and room air for 4 weeks and the preventive and therapeutic effects of NAMPT inhibition were tested in the monocrotaline and Sugen-hypoxia models of PH. The effects on NAMPT activity on proliferation, migration, apoptosis and calcium signaling were tested in human pulmonary artery smooth muscle cell (hPASMC). Results Plasma and mRNA and protein levels of NAMPT were increased in the lungs and isolated pulmonary artery endothelial cells (PAECs) from PAH patients, as well as in lungs of rodent models of pulmonary hypertension (PH). Nampt+/− mice were protected from hypoxia-mediated PH. NAMPT activity promoted human pulmonary artery smooth muscle cell (hPASMC) proliferation via a paracrine effect. In addition, recombinant NAMPT stimulated hPASMC proliferation via enhancement of store-operated calcium entry by enhancing expression of Orai2 and STIM2. Finally, inhibition of NAMPT activity attenuated monocrotaline and Sugen hypoxia induced PH in rats. Conclusions Our data provide evidence that NAMPT plays a role in pulmonary vascular remodeling and its inhibition could be a potential therapeutic target for PAH.

Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity

“…First, that at pharmacological doses, NAM has the potential to function as a PARP inhibitor (41). Second, NAMPT is considered a driver of pulmonary vascular remodeling and potentially a target to be inhibited to maintain lung health of some people at risk for COVID-19 (42). Thus, in order to maximize the likelihood of success in human CoV prevention and treatment trials, care should be taken to carefully compare efficacy and dose-dependence of NR, SBI and NAM with respect to control of cytokine storm and antiviral activities in vivo.…”

Coronavirus infection and PARP expression dysregulate the NAD Metabolome: an actionable component of innate immunity

“…First, that at pharmacological doses, NAM has the potential to function as a PARP inhibitor (46). Second, NAMPT is considered a driver of pulmonary vascular remodeling and potentially a target to be inhibited to maintain lung health of some people at risk for COVID-19 (47). Thus, in order to maximize the likelihood of success in human CoV prevention and treatment trials, care should be taken to carefully compare efficacy and dose-dependence of NR, SBI, NAM with respect to control of cytokine storm and antiviral activities in vivo.…”

Ion Channels in Pulmonary Hypertension: A Therapeutic Interest?

“…STIM2 and Orai2 upregulation in this phenotypic transition enhance SOCE in PASMC and consequently PASMC proliferation [ 200 ]. Recently, nicotinamide phosphoribosyltransferase (NAMPT), a cytozyme, has been described as regulating intracellular nicotinamide adenine dinucleotide levels, the cellular redox state, cell proliferation and apoptosis level [ 201 ]. In addition, the recombinant NAMPT stimulates human PASMC proliferation via an enhancement of SOCE by upregulation of Orai2 and STIM2 expression [ 201 ].…”