C-Type Natriuretic Peptide Preserves Vascular and Cardiac Function in Sepsis

BACKGROUND: Sepsis is a life-threatening condition and a major cause of mortality in intensive care units worldwide, a clear unmet medical need. CNP (C-type natriuretic peptide) regulates inflammation and cardiovascular homeostasis, but its involvement in sepsis pathogenesis is not fully elucidated. This study investigated the intrinsic role of CNP, and therapeutic potential of the peptide, in offsetting the pathogenesis of sepsis. METHODS: Plasma concentrations of CNP, and its N-terminal cleavage product NT-proCNP (N-terminal pro-CNP), were measured in sepsis patients. Cardiac function, vascular hemodynamics, endothelial integrity, and biomarkers of inflammation were analyzed in wild-type, endothelium-restricted (ecCNP −/− ), or cardiomyocyte-restricted (cmCNP −/− ) CNP knockout animals, or global NPR (natriuretic peptide receptor)-C −/− deficient mice, in etiologically distinct models of sepsis. CNP (0.2 mg/kg per d) was infused to rescue any adverse phenotype and probe therapeutic potential. RESULTS: Circulating (NT-proCNP) increased in sepsis patients and was associated with reduced disease severity. ecCNP −/− mice exhibited an aggravated phenotype compared with wild-type mice in experimental sepsis, exemplified by impaired microcirculatory flow, edema, and increased expression of inflammatory biomarkers. In addition, cmCNP −/− animals showed overt cardiac dysfunction following lipopolysaccharide treatment. This worsened phenotype was mirrored in NPR-C −/− mice, implying that this cognate NPR subtype underpins the salutary actions of endogenous CNP. Pharmacological CNP administration improved microvascular perfusion, cardiac output, and inflammation in wild-type and ecCNP −/− , but not NPR-C −/− , mice. CONCLUSIONS: Endogenous CNP plays a protective role in sepsis by preserving microvascular perfusion, reducing inflammation, maintaining endothelial integrity, and sustaining cardiac function via NPR-C. Pharmacologically targeting CNP signaling warrants further evaluation as a potential therapeutic opportunity in sepsis.