Caloric Restriction Attenuates Oxidative Injury but Fails to Reverse Established Cardiac Remodeling in Atrial Natriuretic Peptide Receptor 1-Deficient Mice †

Background: Caloric restriction (CR) is a powerful non-pharmacologic intervention known to extend lifespan and improve cardiovascular health. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) exert antihypertrophic and antifibrotic effects through natriuretic peptide receptor 1 (NPR1), a guanylyl cyclase receptor that generates cyclic GMP (cGMP). Whether intact NPR1 signaling is required for the cardioprotective effects of CR remains unknown. Methods: NPR1 knockout (KO), heterozygous KO (+/−), and wild-type (WT) littermate mice were subjected to a CR regimen (20% caloric reduction for 2 weeks, then 40% for 2 weeks). WT mice were subjected to transverse aortic constriction (TAC) to model acute pressure overload, whereas NPR1-deficient mice were studied in the setting of established genetic cardiomyopathy. Cardiac structure, function, fibrosis, apoptosis, ATP levels, oxidative and ER stress, and signaling pathways (cGMP, eNOS/NO/sGC) were assessed by echocardiography, histology, biochemical assays, and Western blotting. Results: In WT mice, CR significantly attenuated TAC-induced hypertrophy, preserved cardiac function, reduced fibrosis, and decreased oxidative and ER stress. In contrast, CR did not attenuate or reverse established NPR1-deficiency-induced hypertrophy, fibrosis, or dysfunction, despite reducing oxidative stress and ER stress. CR preserved ATP content in NPR1 KO hearts, but cGMP levels remained profoundly depressed (~90% reduction). Compensatory activation of NO-sGC signaling was observed in NPR1 KO hearts, but this response was insufficient to restore myocardial cGMP levels or limit structural remodeling. Conclusions: These findings indicate that intact NPR1-cGMP signaling is required for CR-mediated protection against pressure-overload–induced cardiac remodeling, whereas CR alone is insufficient to reverse established, genetically programmed cardiomyopathy in the absence of NPR1. Although CR reduces oxidative stress, ER stress, and preserves myocardial ATP, these adaptations are insufficient to compensate for the loss of NPR1-cGMP signaling in reversing established pathological cardiac remodeling. Thus, the cardioprotective efficacy of CR appears to be context-dependent and may require intact natriuretic peptide signaling.