Abstract
B-type natriuretic peptide (BNP) is secreted by ventricular cardiomyocytes in response to various types of cardiac stress and has been used as a heart failure marker. In septic patients, increased BNP suggests poor prognosis; however, no causal link has been established. Among various effects, BNP decreases systemic vascular resistance and increases natriuresis that leads to lower blood pressure. We previously observed that JNK inhibition corrects cardiac dysfunction and suppresses cardiac BNP mRNA in endotoxemia. In this study, we investigated the transcriptional mechanism that regulates BNP expression and the involvement of plasma BNP in causing septic hypotension. Our in vitro and in vivo findings confirmed that activation of JNK signaling increases BNP expression in sepsis via direct binding of c-Jun in activating protein–1 (AP-1) regulatory elements of the Nppb promoter. Accordingly, genetic ablation of BNP, as well as treatment with a potentially novel neutralizing anti-BNP monoclonal antibody (19B3) or suppression of its expression via administration of JNK inhibitor SP600125 improved cardiac output, stabilized blood pressure, and improved survival in mice with polymicrobial sepsis. Therefore, inhibition of JNK signaling or BNP in sepsis appears to stabilize blood pressure and improve survival.
Highlights
Sepsis results from the overwhelming systemic response to infection resulting in hemodynamic instability, reduced tissue perfusion, and multiple organ dysfunction [1]
Deletion of the Nppb gene was confirmed by lack of amplification of B-type natriuretic peptide (BNP) mRNA by reverse transcription PCR (RT-PCR) in hearts obtained from the BNP-KO mice (Figure 1B) and undetectable plasma BNP levels (Figure 1C)
We observed that, while end-diastolic volume (EDV) was reduced in WT controls within 6 hours of CLP surgery, which progressed further by 12 hours, BNP-KO mice did not experience a reduction in EDV, which was significantly increased at 6 and 12 hours compared with WT controls (Figure 1G)
Summary
Sepsis results from the overwhelming systemic response to infection resulting in hemodynamic instability, reduced tissue perfusion, and multiple organ dysfunction [1]. The systemic host response promotes cardiovascular dysfunction, resulting in increased vascular permeability, relative hypovolemia, and reduced arterial pressure. Circulating B-type natriuretic peptide (BNP) has been proposed as a biomarker associated with poor prognosis and myocardial depression resulting from severe sepsis [4, 5, 8, 9]. Lower end-diastolic volume (EDV), impaired myocardial strain, reduced cardiac output (CO), and hypotension — which occur in the CLP model — can be regulated by natriuretic peptide signaling and are altered in coordination with plasma BNP [10, 13]. BNP has been shown to regulate blood pressure and cardiac load [10], there is no study that has identified the pathways leading to increased BNP expression in sepsis, and neither has aberrant upregulation of BNP in sepsis been tested as a major therapeutic target for septic hypotension
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