title: Angiotensin II down-regulates natriuretic peptide receptor-A expression and guanylyl cyclase activity in H9c2 (2-1) cardiac myoblast cells: Role of ROS and NF-κB.
abstract: Atrial natriuretic peptide (ANP)/natriuretic peptide receptor-A (NPR-A) system is suggested as an endogenous anti-hypertrophic protective mechanism of the heart. We have shown previously that Angiotensin II (ANG II), an effector molecule of renin-angiotensin-aldosterone system, down-regulates NPR-A expression and its activity in vivo rat heart. However, the underlying mechanism by which ANG II down-regulates NPR-A expression in the heart is not well understood. Hence, the present investigation was aimed to determine whether ANG II-stimulated reactive oxygen species (ROS) and NF-κB are involved in the down-regulation of NPR-A activity in H9c2 (2-1) cardiac myoblast cells. The H9c2 (2-1) cardiac myoblast cells were exposed to ANG II (10(-7) M for 20 h) with/or without blocker treatment (losartan-10 µM, N-acetyl cysteine (NAC)-10 mM and pyrrolidine dithiocarbamate (PDTC)-100 µM). On exposure, ANG II induced a significant decrease (P < 0.001) in the expression of Npr1 (coding for NPR-A) gene and NPR-A receptor-dependent guanylyl cyclase (GC) activity. The level of expression of proto-oncogenes (c-fos, c-myc, and c-jun) and natriuretic peptides (ANP and BNP) was increased in ANG II-treated cells when compared with control cells. Interestingly, ANG II-dependent repression of Npr1 gene expression and guanylyl cyclase (GC) activity was completely restored on treatment with losartan, while only a partial reversal was observed in NAC- and PDTC-co-treated cells. In conclusion, the results of this study suggest that ROS-mediated NF-κB activation mechanism is critically involved in the ANG II-mediated down-regulation of NPR-A expression and its GC activity.
authors.affiliation: Department of Biochemistry, University of Madras, Guindy Campus, Chennai, Tamil Nadu, 600 025, India.
authors.forename: Venkatachalam
authors.initials: V
authors.lastname: Gopi
authors.affiliation: Department of Biochemistry, University of Madras, Guindy Campus, Chennai, Tamil Nadu, 600 025, India.
authors.forename: Vimala
authors.initials: V
authors.lastname: Subramanian
authors.affiliation: Department of Biochemistry, University of Madras, Guindy Campus, Chennai, Tamil Nadu, 600 025, India.
authors.forename: Senthamizharasi
authors.initials: S
authors.lastname: Manivasagam
authors.affiliation: Department of Biochemistry, University of Madras, Guindy Campus, Chennai, Tamil Nadu, 600 025, India. vellaie@unom.ac.in.
authors.forename: Elangovan
authors.initials: E
authors.lastname: Vellaichamy
mesh_terms: D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000378:metabolism*; D032386:Myoblasts, Cardiac / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017461:Receptors, Atrial Natriuretic Factor / Q000096:biosynthesis*
chemical_list: D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D009320:Atrial Natriuretic Factor; D019255:NADPH Oxidases; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A
keywords: Angiotensin II; Guanylyl cyclase-A; Natriuretic peptide receptor-A; Nuclear factor-kappa B (NF-κB); Reactive oxygen species (ROS)