Abstract 16704: High Levels of Extracellular Nampt Produce Cardiac Hypertrophy and Ventricular Remodeling
Background: Nampt is an important coenzyme involved in cellular redox reactions. While inside the cell Nampt (iNampt) functions as a rate limiting enzyme in the NAD salvage pathway, outside the cell (eNampt) it acts as a pro-inflammatory cytokine. High circulating levels of Nampt are reported in many pathological conditions such as obesity, diabetes, atherosclerosis and chronic inflammation. This study was designed to examine the role of Nampt in the development of cardiac hypertrophy.
Methods and Results: We studied the hypertrophic response of Nampt-heterozygous (+/-) knockout and cardiac-specific over expressing Nampt transgenic (Nampt-Tg) mice to agonist (isoproterenol and angiotensin-II) infusion. The results showed that Nampt (+/-) mice were protected to agonist-mediated hypertrophic response, and Nampt-Tg mice spontaneously developed cardiac hypertrophy at 6-8 wks of age. To understand the underlying mechanism of Nampt-mediated hypertrophy, we treated cardiomyocytes with recombinant eNampt or over expressed with a Nampt synthesizing adenovirus vector (Ad-Nampt), which elevated cellular iNampt levels. In both conditions, we found that Nampt produced cardiomyocyte hypertrophy. This pro-hypertrophic effect of eNampt and Ad-Nampt was completely blocked by addition of a Nampt-blocking antibody into cultures, thus suggesting that Nampt was invoking hypertrophic response of cardiomyocytes by acting on cell surface receptors. In addition, we found that there was increased Nampt level in the supernatant of cardiomycytes cultures subjected to stress stimulation by either serum starvation or H2O2 treatment, thus indicating that cardiomyocytes were capable of releasing Nampt under stress conditions. Exploration of the signaling pathways leading to Nampt-induced cardiac hypertrophy and fibrosis revealed that there was increased activation of mitogen activated protein kinases namely JNK1, p38 and ERK in Nampt treated cardiomyocytes. This was also associated with increased calcineurin levels and NFAT localization into the nucleus.
Conclusion: These data demonstrate that circulating Nampt or Nampt secreted from cardiomyocytes during stress is a positive regulator of cardiac hypertrophy and adverse ventricular remodeling.
- © 2012 by American Heart Association, Inc.