Fig. 7

Schematic showing the potential beneficial effects of sacubitril/valsartan combination in a genetic model of obesity and early diabetes with established diastolic dysfunction. The prodrug sacubitril is converted to sacubitrilat (LBQ657) in vivo via de-ethylation by esterases, and is a known inhibitor of neprilysin and ANP and BNP degradation (1). By enhancing ANP and BNP levels and subsequent conversion of GTP to cGMP (2), sacubitrilat improves vasorelaxation and vascular regeneration and decreases RAAS/sympathetic tone and Notch1-dependent inflammatory signaling (3). Additional enhancement of IL-4 receptor signaling by sacubitrilat (4), but not valsartan, suppresses macrophage-mediated inflammatory responses and enhances metabolic functions in cardiomyocytes through an IL-4/IL-13 hybrid receptor (5). Valsartan, on the other hand, blocks AT1R, and decreases aldosterone levels and MR signaling (6), resulting in improved vascular relaxation and decreased RAAS, sympathetic tone and Notch1-dependent inflammatory responses (7). Collectively, this drug combination reduces diastolic dysfunction (8) and vascular stiffness (9) by reducing aortic stiffness, oxidative stress, inflammatory responses, and cardiac fibrosis (10 and 11) by modulating ANP/BNP, AT1R, MR and IL-4/IL-13 mediated signaling in a genetic model of obesity and early diabetes. ANP, Atrial Natriuretic Peptide; AngII, Angiotensin II; Aldo, Aldosterone; BNP, Brain Type Natriuretic peptide; AT1R, Angiotensin type 1 Receptor; MR, Mineralocorticoid Receptor; IL-4, Interleukin-4; IL-13, Interleukin-13; ATP, Adenosine Triphosphate; GTP, Guanosine triphosphate; cGMP, cyclic guanosine monophosphate; RAAS: Renin–Angiotensin–Aldosterone System; Notch1, Notch homolog 1 translocation-associated (drosophila)