Endogenous C-type natriuretic peptide mitigates vascular dysfunction, inflammation and cardiomyopathy during endotoxemia and polymicrobial sepsis

Sepsis is one of the leading causes of death worldwide yet there are limited treatment options for this disease. There has been increasing interest in therapies targeting the microvasculature to improve tissue perfusion and reduce organ damage that often persists despite macrohemodynamic stabilization. CNP is a cardioprotective vasodilator peptide that has been shown to regulate blood pressure, inflammation, and cardiac contractility. Plasma levels of CNP are elevated in patients with sepsis but little is known about the function of this peptide in this syndrome.

LPS inoculation and caecal ligation and puncture (CLP) were performed in mice lacking endothelial-derived CNP (ecCNP ^-/-), cardiomyocyte-derived CNP (cmCNP ^-/-) and natriuretic peptide receptor C (NPR-C ^-/-). A subset of animals were also treated with CNP via mini-pump (0.2mg/kg/day). Cardiovascular hemodynamics, biochemical and inflammatory markers were measured at 24 hr post sepsis induction.

ecCNP ^-/- mice exhibit impaired endothelial function, reduced blood flow and greater expression of inflammatory markers despite exhibiting a higher blood pressure than WT littermates. NPR-C ^-/- mice display similar vascular disturbances to ecCNP ^-/- as well as a greater decline in cardiac function. cmCNP ^-/- mice also present with worse diastolic function following LPS challenge. NPR-C ^-/- mice exhibit more vascular leak in addition to reduced expression of gap and tight junctions. CNP infusion improves blood flow, diastolic function and inflammation.

Our findings indicate endogenous endothelial derived CNP plays a protective role in sepsis by maintaining blood flow, reducing inflammation, preventing oedema and regulating heart function via NPR-C. This peptide may offer a novel therapeutic opportunity in sepsis.