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

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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.

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Acknowledgments

Dr. EV greatly acknowledges Council of Scientific and Industrial Research (CSIR), and University grants commission (UGC), New Delhi, India for their research support. The authors are grateful to Dr. Ramamurthy, Director, National Centre for Ultrafast Processes, University of Madras, India, for her help in confocal analysis.

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  1. Department of Biochemistry, University of Madras, Guindy Campus, Chennai, 600 025, India

    Arumugam Parthasarathy, Venkatachalam Gopi, Subramanian Umadevi, Anoop Simna, Mohammed Jainuddin Yousuf Sheik, H. Divya & Elangovan Vellaichamy

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  1. Arumugam Parthasarathy
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Parthasarathy, A., Gopi, V., Umadevi, S. et al. Suppression of atrial natriuretic peptide/natriuretic peptide receptor-A-mediated signaling upregulates angiotensin-II-induced collagen synthesis in adult cardiac fibroblasts. Mol Cell Biochem 378, 217–228 (2013). https://doi.org/10.1007/s11010-013-1612-z

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