Abstract 13322: Caloric Restriction Inhibits Oxidative Stress and Endoplasmic Reticulum Stress but is not Sufficient to Reduce Cardiac Remodeling in the Absence of Atrial Natriuretic Peptide Signaling
Caloric restriction (CR) is a robust dietary intervention known to enhance cardiovascular health and protect the heart against pathological stresses, but the underlying mechanism remains unclear. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones that regulate blood pressure and cardiac homeostasis via the natriuretic peptide receptor-A (NPR1). CR was shown to induce an early increase of circulating ANP and to enhance the hemodynamic effects of exogenous ANP in patients. Our preliminary data show that CR can increase the expression of ANP and BNP in the mouse heart, raising the possibility that the cardioprotective effects of CR are mediated by ANP/BNP signaling. We tested this hypothesis in the present study using mice lacking NPR1 (NPR1 -/-). We subjected NPR1-/- mice and their wild type (WT) littermates to a CR regimen that reduces caloric intake by 20%-40% for 4 weeks. CR dramatically inhibited oxidative stress and endoplasmic reticulum (ER) stress in NPR1-/- mouse hearts as shown by several different markers including oxidized proteins, nitrotyrosine, 4-Hydroxynonenal, CHOP, BiP, PERK and IRE1α. Furthermore, CR reduced cardiac ATP content by 20.2%, but it prevented NPR1 deficiency-induced severe depletion of ATP, which correlated with a partially restored expression of ATP5g2, a subunit of mitochondrial ATP synthase. However, despite these seemingly beneficial effects, CR failed to decrease NPR1 deficiency-induced pathological cardiac remodeling as evidenced by the elevated heart to body weight ratio, fibrosis and impaired cardiac function. Consistently, CR increased cyclic guanosine monophosphate (cGMP) levels in WT mice but not in NPR1 -/- mice. Together, these results suggested that an intact ANP/NPR1/cGMP signaling is required for CR to provide maximal cardiac benefits; without NPR1, CR is unable to reduce cardiac remodeling despite its robust ability to inhibit oxidative stress and ER stress and to improve cardiac energy metabolism.
- © 2013 by American Heart Association, Inc.