Angiotensin II receptor antagonism reverts the selective cardiac BNP upregulation and secretion observed in myocarditis

Abstract

The cardiac natriuretic peptides atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are discoordinately regulated in myocardial inflammation associated with acute allograft rejection in humans and during in vitro exposure of cardiocyte cultures to some proinflammatory cytokines. We used experimental autoimmune myocarditis (EAM) to determine whether the discoordinate regulation of ANF and BNP was specific to the situations above or was generally associated with other types of myocardial inflammation. The dependency of this process to angiotensin signaling was also determined, given that previous work demonstrated beneficial effects of the angiotensin receptor blocker olmesartan in myocarditis. Histopathological changes, plasma and cardiac ANF, BNP, and selected cytokines gene expression as well as plasma cytokine levels using a cytokine array were determined in EAM, angiotensin receptor blocker-treated, and control rats. It was found that EAM specifically increases BNP but not ANF circulating levels, thus mimicking the findings in acute cardiac allograft rejection and the effect of some proinflammatory cytokines on cardiocyte cultures in vitro. Plasma cytokine array and real-time PCR revealed that lipopolysaccharide-induced CXC chemokine, monocyte chemotactic protein-1, and tissue inhibitor of metalloproteinase-1 were increased in plasma and in the myocardium of EAM rats. Olmesartan treatment reversed virtually all neuroendocrine and histopathological cardiac changes induced by EAM, thus providing a mechanistic insight into this phenomenon. It is concluded that the inflammatory process contributes specific cytokines, leading to the disregulation of cardiac ANF and BNP production observed during myocardial inflammation, and that this process is angiotensin receptor 1 dependent. cytokines; brain natriuretic peptide; atrial natriuretic factor THE NATRIURETIC PEPTIDES atrial natriuretic factor (ANF; and atrial natriuretic peptide) and brain natriuretic peptide (BNP) are cardiac hormones that increase in blood in pathophysiological states such as arterial hypertension and chronic congestive heart failure (17, 26). However, we previously found that during an acute cardiac allograft rejection episode in humans, plasma BNP may be elevated above prerejection levels independent of hemodynamic parameters, whereas plasma ANF levels did not change in unison with BNP. Successful treatment of the acute rejection episode reversed the increased circulating BNP, suggesting that cytokines released from activated T lymphocytes may stimulate BNP secretion from cardiocytes (15).In support of this view, we found that the conditioned medium derived from a mixed lymphocyte reaction, an in vitro model of transplantation immunity, stimulates BNP mRNA content and BNP secretion in rat neonatal cardiocyte cultures but did not produce similar changes in ANF gene expression or secretion (13). It was further determined that proinflammatory cytokines, such as IL-1␤ and TNF-␣, specifically stimulated BNP mRNA and BNP secretion in ...

Cardiac Natriuretic Peptides Gene Expression and Secretion in Inflammation

“…We have used experimental autoimmune myocarditis in rats to determine if the discoordinate regulation of ANF and BNP is observed in such pathology that histologically resembles giant cell myocarditis. 29 Experimental autoimmune myocarditis specifically increased BNP, but not ANF circulating levels, thus resembling findings made in acute cardiac allograft rejection and the effect of some proinflammatory cytokines on cardiocyte cultures, suggesting that inflammatory processes are generally associated with the disregulation of cardiac ANF and BNP synthesis and secretion.…”

Retrospective Evaluation of 28 Patients Diagnosed as Acute Myo/Pericarditis: Properties of an Epidemia

“…Bu nedenle kalp yetersizliğine neden olan miyokardit ve dilate kardiyomiyopatide serum düzeyleri artar. 31 Çalışma-mızda kardiyomiyopatisi olan altı hasta ve masif perikardiyal efüzyonu olan bir hasta olmak üzere, toplam yedi hastada (%25) NT-ProBNP düzeyi >140 pg/ml saptandı.…”

Republished: Pathogenesis and diagnosis of myocarditis

“…The prohormone BNP is only released to the circulation when the ventricles become dilated, hypertrophic or during other conditions that induce wall distension and stretching, and by neurohormonal activation. BNP has been found to be elevated in the serum of patients with myocarditis and DCM 53 57 58. Overall, BNP and NT-proBNP are biomarkers with a high sensitivity and specificity in predicting heart failure in a number of cardiovascular conditions including myocarditis and DCM.…”