Citations 2
Abstract 4141553: CD38 Deficiency Increases NAD Levels And Improves Pulmonary Hypertension
Thompson, Katie, Tang, Haiyang , Chini, Eduardo N. , Naidu, Samisubbu R. , Desai, Ankit A.
Circulation | November 14, 2024 | Volume: 150 | Issue: Suppl_1 | Pages: No page available
10.1161/circ.150.suppl_1.4141553
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.
A nitroalkene derivative of salicylate alleviates diet-induced obesity by activating creatine metabolism and non-shivering thermogenesis
Cal, Karina, Leyva, Alejandro , Rodriguez-Duarte, Jorge, Ruiz, Santiago , Santos, Leonardo, Colella, Lucía, Ingold, Mariana , Vilaseca, Cecilia, Galliussi, Germán , Handy, Rachel, Reis, Larissa Menezes dos , Espasandín, Camila , Dapueto, Rosina , Thompson, Katie, Agorrody, Guillermo , DeVallance, Evan , Meadows, Ethan , Barbosa, Gabriele Santana, Souza, Leonardo Osbourne Lai de , Chichierchio, Marina Santos , Valez, Valeria , Aicardo, Adrián , Jakobsen, Steen, Kamaid, Andrés , Porcal, Williams , Calliari, Aldo , Wang, Yekai, Hollander, John M. , White, Thomas A. , Radí, Rafael , O’Doherty, Robert M. , Holloway, Graham P. , Kelley, Eric, Chini, Eduardo N. , Peclat, Thais R , Dos Reis, Larissa Menezes , Thompson, Katie L., Chichierchio, Marina Santos , Aicardo, Adrián , Contreras, Paola , White, Thomas A , Quijano, Celia , Moraes-Vieira, Pedro , Mori, Marcelo A , Lopez, Gloria V , Batthyány, Carlos , Chini, Eduardo Nunes , Escande, Carlos , Rodriguez‐Duarte, Jorge , Ziegler, Lucía , Peclat, Thais , Bresque, Mariana , Handy, Rachel, King, Rachel, Breining, Peter , Lopez, Andres, Lewis, Sara E. , Vendelbo, Mikkel Holm , Verdes, José Manuel , Du, Jianhai , Moyna, Guillermo , Leonardi, Roberta , Camacho-Pereira, Juliana , Durán, Rosario
No container title available | July 12, 2023 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.