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

• Published in: Molecular and cellular biochemistry 2013-06, Vol.378 (1-2), p.217-228
• Main Authors: Parthasarathy, Arumugam, Gopi, Venkatachalam, Umadevi, Subramanian, Simna, Anoop, Sheik, Mohammed Jainuddin Yousuf, Divya, H., Vellaichamy, Elangovan
• Format: Article
• Language: English
• Subjects: Angiotensin; Angiotensin II - physiology; Animals; Atrial Natriuretic Factor - physiology; Biochemistry; Biomedical and Life Sciences; Cardiology; Cell Nucleus - metabolism; Cell Proliferation; Cells, Cultured; Cellular biology; Collagen; Collagen Type I - biosynthesis; Collagen Type III - biosynthesis; Enzymes; Fibroblasts - metabolism; Gene Knockdown Techniques; Heart; Hormones; Life Sciences; Male; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; Medical Biochemistry; Myocardium - cytology; Natriuretic peptides; NF-kappa B - metabolism; Oncology; Peptides; Proteases; Proteins; Public radio; Rats; Rats, Wistar; Reactive Oxygen Species - metabolism; Receptors, Atrial Natriuretic Factor - genetics; Receptors, Atrial Natriuretic Factor - metabolism; RNA, Small Interfering - genetics; Signal Transduction; Translocation; Up-Regulation
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-013-1612-z

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.