Reversal of pulmonary arterial hypertension and neointimal formation by kinin B1 receptor blockade

Abstract

Background This study examined whether BI113823, a novel selective kinin B1 receptor antagonist can reverse established pulmonary arterial hypertension (PAH), prevent right heart failure and death, which is critical for clinical translation. Methods Left pneumonectomized male Wistar rats were injected with monocrotaline to induce PAH. Three weeks later, when PAH was well established, the rats received daily treatment of BI113823 or vehicle for 3 weeks. Results Treatment with BI113823 from day 21 to day 42 after monocrotaline injection reversed established PAH as shown by normalized values of mean pulmonary arterial pressure (mPAP). BI113823 therapy reversed pulmonary vascular remodeling, pulmonary arterial neointimal formation, and heart and lung fibrosis, reduced right ventricular pressure, right heart hypertrophy, improved cardiac output, and prevented right heart failure and death. Treatment with BI113823 reduced TNF-α and IL-1β, and macrophages recruitment in bronchoalveolar lavage, reduced CD-68 positive macrophages and expression of proliferating cell nuclear antigen (PCNA) in the perivascular areas, and reduced expression of iNOS, B1 receptors, matrix metalloproteinase (MMP)-2 and MMP-9 proteins, and the phosphorylation of ERK1/2 and AKT in lung. Treatment with BI113823 reduced mRNA expression of ANP, BNP, βMHC, CGTF, collange-I and IV in right heart, compared to vehicle treated controls. In human monocytes cultures, BI113823 reduced LPS-induced TNF-α production, MMP-2 and MMP-9 expression, and reduced TNF-α-induced monocyte migration. Conclusions We conclude that BI113823 reverses preexisting severe experimental pulmonary hypertension via inhibition of macrophage infiltration, cytokine production, as well as down regulation of matrix metalloproteinase proteins.

Monocrotaline-Induced Pulmonary Arterial Hypertension and Bosentan Treatment in Rats: Focus on Plasma and Erythrocyte Parameters

“…These findings are contradictory to our observation of decreased aldosterone concentration after PAH induction. However, other authors have reported that either the transcripts or levels of natriuretic peptides were elevated in the condition of PAH [ 34 , 35 , 36 , 37 ]. These findings may provide an explanation for the surprisingly low plasma aldosterone level observed in our study simultaneously with unchanged Ang II concentration, as natriuretic peptides are inhibitors of aldosterone synthesis [ 38 ].…”

Preliminary Mechanism of Glial Maturation Factor β on Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension

“…The expression and phosphorylation of VEGFR directly promoted the proliferation of PASMC cultured in vitro and indirectly promoted the proliferation of PASMC through the upregulation of MMP (matrix metalloprotein, MMP)-9. [20] Inflammatory factors such as TNF-𝛼, IL-1𝛽, [21] and CSF2 [22] were also involved in the development of PAH and were associated with the proliferation of PASMC as well as PAEC in the pulmonary vasculature. [14,16] Glia maturation factor 𝛽 (GMF𝛽) is a highly conserved amino acid polypeptide between humans and rodents, which is essential for glial cells and neuron growth and differentiation.…”

Kinin B1 receptor blockade attenuates hepatic fibrosis and portal hypertension in chronic liver diseases in mice

“…B2R activated by bradykinin has been shown to attenuate liver damage and fibrosis development in a rat model of chronic liver injury [8]. By contrast, B1Rs are involved in diverse pathological processes, including inflammation, platelet activation, smooth muscle contraction, increased vascular permeability, oedema, pain, cytokine and chemokine release, cell proliferation, and tissue remodelling, responses that are key components of liver fibrosis [6,7,[9][10][11][12][13]. Furthermore, in contrast to the B2 receptor mediated relaxation to bradykinin, B1Rs are induced in the rat portal vein and stimulation triggers vasoconstriction via the cyclooxygenase-2 (COX-2) pathway [14].…”