Grant Abstract: Role of vascular smooth muscle Bcl11b in arterial stiffness

Grant Number: 3R01HL136311-04S1
PI Name: Seta
Project Title: Role of vascular smooth muscle Bcl11b in arterial stiffness

Abstract: Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor for the activity of enzymes involved in cellular metabolic homeostasis, redox balance, DNA synthesis, and stress response. NAD+ is synthetized de novo from tryptophan, but its function is so fundamental to cellular function that mammals evolved a salvage pathway to continuously replenish intracellular NAD+ using a variety of substrates. Among NAD+ precursors, nicotinamide (NAM), nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR) are commercially available as dietary supplements; however, we do not fully understand the full spectrum of their biological effects, specifically on the cardiovascular system, which will be the focus of this research proposal. Of clinical importance, NAD+ levels have been shown to drastically decrease with obesity and aging, which are the highest risk factors for cardiovascular disease (CVD). We postulate that replenishing intracellular NAD+ via dietary supplements is a viable approach to attenuating CVD, which remain the primary cause of morbidity and mortality in an increasingly obese and aging American population. Recent evidence indicate that administering NAM and NMN to experimental animals significantly increases NAD+ levels in heart and fat, preventing diabetes and diabetic heart failure in obese mice/rats. Moreover, NMN has been shown to prevent arterial stiffening and hypertension in aged mice. However, whether dietary supplementation of NMN or NR increases NAD+ levels in the vasculature and whether these increased levels lead to molecular mechanisms with potentially beneficial vascular effects are not fully understood. The goal of this supplemental proposal is to investigate whether dietary supplementation of NMN, NR, or a combination of the two supplements to mice increases NAD+ levels in the vasculature (Aim 1). We will also determine whether this supplementation can preserve vascular function, measured as arterial compliance and blood pressure, in obese and aged mice, by increasing NAD+ levels in vascular cells and activating downstream anti-inflammatory and anti-oxidant pathways (Aim 2). Successful completion of these preclinical, proof-of concept studies will fill a gap in knowledge on the vascular effects of NAD+ precursors and will guide rational use of NAD+ precursors (NMN, NR) as dietary supplements.

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