MANP: A Novel Designer Natriuretic Peptide for Cardiometabolic Disease

Abstract

Introduction: Atrial natriuretic peptide (ANP) is a cardiac hormone that plays an important role in blood pressure regulation via the guanylyl cyclase receptor A (GC-A) and cGMP. ANP also induces lipolysis in vitro and in vivo and we have reported that an ANP genetic variant (rs5068), which is associated with higher circulating levels of ANP is also associated with lower prevalence of metabolic syndrome in a US general population. MANP is a newly Mayo engineered designer natriuretic peptide (NP) consisting of the native ANP with 12-amino-acid C-terminus extension. Studies in canines established that MANP has greater blood pressure (BP) lowering, natriuretic, and aldosterone-suppressing properties than ANP. To date, the metabolic actions of MANP remain unexplored. Hypothesis: MANP possesses not only cardiovascular but also metabolic properties. Methods: For in vitro studies, human embryonic kidney (HEK) 293 cells transfected with either GC-A or guanylyl cyclase receptor B (GC-B), and human subcutaneous and visceral preadipocytes were assessed for cGMP production by MANP. Cells were treated with 10 M, 10 8 M, or 10 M MANP for 10 min. In vivo, we defined the BP lowering and metabolic actions of acute MANP (30 pmol/kg/min, iv) or vehicle in normal Sprague-Dawley rats. After equilibration (45 minutes) MANP was administered iv for 75 min. Results: In vitro, MANP induced cGMP production in GC-A but not GC-B expressing HEK cells. MANP significantly increased cGMP in human subcutaneous and visceral preadipocytes. In vivo, infusion of MANP significantly increased plasma MANP levels compared to vehicle (222 vs 10 pg/ml, p50.019). MANP infusion decreased BP when compared to baseline (91 vs 100 mmHg, p50.016), vehicle had no significant effect (92 vs 95 mmHg, p5 0.19). Plasma levels of nonesterified fatty acids (NEFA), a marker for lipolysis, tended to be higher after infusion of MANP than after vehicle (598 vs 462 mg/dl, p5 0.06). Conclusions: The designer NP MANP demonstrates specificity for GC-A and activates cGMP in human subcutaneous and visceral preadipocytes. In vivo, MANP possesses blood pressure lowering actions and causes an increase in NEFA plasma levels suggesting a lipolytic effect. Further studies are warranted to better define the cardiorenal and metabolic actions of MANP and its possible therapeutic roles in cardiometabolic disease which is a risk factor for future heart failure.