BNP not just a biomarker of cardiovascular disease

Abstract: Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are powerful vasodilators, which are secreted by heart muscle cells. BNP and N-terminal proBNP (NT-proBNP) are widely used as diagnostic biomarkers for heart failure (HF) and cardiac dysfunction in clinical medicine. Plasma concentrations of BNP and NT-proBNP correlate with disease severity, development of symptoms, and prognosis in heart failure and coronary heart disease. High plasma concentrations of BNP and NT- proBNP are strong predictors for risk of myocardial infarction and adverse outcomes in patients presenting with acute coronary syndromes. However, whether BNP contributes to the pathogenesis of the cardiovascular disease remains elusive. Preliminary studies indicate that injection of BNP into mice promoted thrombus formation in a FeCl3-induced arterial thrombosis model. BNP also potentiated platelet aggregation in mice and humans. These data suggest that BNP is not only a diagnostic biomarker of the heart failure and coronary heart disease, it may also contribute to the pathogenesis and progression of the cardiovascular disease, especially to the thrombotic event. ANP and BNP are circulating hormones of cardiac origin that play an important role in the regulation of intravascular blood volume and vascular tone through their receptor natriuretic receptor-A (NPRA). NPRA is a membrane-bound guanylyl cyclase that generates cGMP, an important second messenger. In the preliminary studies, it was found for the first time that NPRA is present in platelets, and incubation of platelets with BNP increased intracellular cGMP concentrations. Based on these findings, the central hypothesis to be tested is that BNP is not only a biomarker of the cardiovascular disease, but also promotes thrombosis through platelet activation, and thereby influences adverse cardiovascular events. This hypothesis will be tested in the following specific aims: Aim 1 is to establish BNP as an important mediator of thrombosis, and elucidate the mechanism of BNP-induced platelet activation. The working hypothesis is that BNP potentiate platelet activation and thrombosis via its receptor NPRA. Intracellular signaling by natriuretic peptides is typically mediated by PKG II. NPRA deficient and PKG II deficient mice will be used to test the hypothesis that NPRA/cGMP/PKG II mediates the effect of BNP on platelet activation and thrombosis in vivo. Aim 2 is to investigate the role of NPRA/cGMP in platelet activation and thrombosis. The preliminary data indicate that agonist-induced platelet aggregation, in the absence of exogenous ANP or BNP, was impaired in the NPRA-/- mice. This aim is to investigate whether NPRA contributes to thrombosis under physiological conditions without injection of BNP. Completion of these studies will provide evidence that BNP may not only serve as important biomarkers of cardiovascular disease, but also mediate adverse events by effects on platelet function. A novel mechanism of platelet activation and thrombosis will also be identified.