Suppression of atrial natriuretic peptide/natriuretic peptide receptor-A-mediated signaling upregulates angiotensin-II-induced collagen synthesis in adult cardiac fibroblasts

Abstract

Cardiac hormone atrial natriuretic peptide (ANP) and its receptor natriuretic peptide receptor-A (NPR-A) system acts as an intrinsic negative regulator of abnormal extracellular matrix (ECM) remodeling in the heart. However, the underlying mechanism by which ANP/NPR-A system opposes the ECM remodeling in the diseased heart is not well understood. Here, we investigated the anti-fibrotic mechanism of ANP/NPR-A in fibrotic agonist Angiotensin- II (ANG II)-treated adult cardiac fibroblast (CF) cells. Normal and NPR-A-suppressed adult CF cells were treated with ANG II (10(-7) M) in the presence and absence of ANP (10(-8) M) for 24 h. Total collagen concentration, activity and expression of MMP-2 and MMP-9, and nuclear translocation of Nuclear factor-kappaB (NF-κB-p50) were studied. NPR-A-suppressed adult CF cells exhibited a more pronounced increase in collagen production, ROS generation, and NF-κB-p50 nuclear translocation as compared to adult CF cells treated with agonist alone. ANP co-treatment significantly reverses the agonist-induced above changes in normal adult CF cells, while it failed to reverse the agonist-induced collagen synthesis in the NPR-A-suppressed adult CF cells. The cGMP analog (8-bromo-cGMP) treatment significantly attenuated the agonist-induced collagen synthesis both in normal and NPR-A-suppressed adult cells. The results of this study suggest that ANP/NPR-A signaling system antagonizes the agonist-induced collagen synthesis via suppressing the activities of MMP-2, MMP-9, ROS generation, and NF-κB nuclear translocation mechanism.

Safflower Yellow Inhibits Angiotensin II–Induced Adventitial Fibroblast Proliferation and Migration

“…However, the exact mecha nism behind the regulators and the underlying mecha nisms controlling the expression and activation of these proteins in AFs are poorly understood. It has been shown that Ang II induces an increase in the synthesis of collagen I and collagen III in fibroblasts (27) and ERK induced collagen I and collagen III expression in cultured renal interstitial fibroblasts (28). In this study, we found that Ang II significantly induced the expression of collagen I and collagen III at both the protein and mRNA level and increased the expression of AP1 protein in AFs.…”

Renal C3 Complement Component: Feed Forward to Diabetic Kidney Disease

“…The network also shows NF-kB acting on up-regulated CCR2, a receptor involved in monocyte activation [50], on up-regulated CXCL1, the prototypical neutrophil chemokine [51], on up-regulated CXCL10, a leukocyte chemoattractant [52], and on up-regulated CCL19, a chemokine for dendritic cells and T lymphocytes [53]. NF-kB, activated by IL1R, the receptor for IL-1 [54], acts on up-regulated collagen I gene, a redundant effect mediated by C3a, C5a, and IL-1 [55]. C5a also acts on the fibronectin gene [56], and presumably its cognate protein, which can then activate up-regulated BMP1 and promote the formation of collagens I and III [57].…”

Impaired sinoatrial node function and increased susceptibility to atrial fibrillation in mice lacking natriuretic peptide receptor C

“…; Parthasarathy et al . ). The antifibrotic effects of NPs are also thought to involve alterations in activity or expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases, proteins that play a critical role in the maintenance of the extracellular matrix (Kassiri & Khokha, ), in fibroblasts (Tsuruda et al .…”

“…; Parthasarathy et al . ). It is presently unknown whether any of these effects specifically involve NPR‐C or whether expression of these proteins is altered in NPR‐C −/− mice.…”