title: Downregulation of natriuretic peptide clearance receptor mRNA in vascular smooth muscle cells by angiotensin II.
abstract: Angiotensin II can downregulate atrial natriuretic peptide binding to rat vascular smooth muscle cells (VSMCs), but the mechanism is not known. Because protein kinase C (PKC) mimetic phorbol myristate acetate (PMA) can destabilize natriuretic peptide clearance receptor (NPR-C) mRNA and angiotensin II activates several PKC isoforms in VSMCs, we hypothesized that angiotensin II treatment decreases NPR-C mRNA stability and exerts this effect through PKC. This study demonstrated that angiotensin II induced time- and concentration-dependent downregulation of NPR-C, which was completely inhibited by an angiotensin II type I receptor blocker losartan. NPR-C mRNA disappearance rate over 6 h was nearly doubled by exposure of VSMCs to 100 nm angiotensin II, compared with that observed after inhibition of RNA synthesis alone. However, this response to angiotensin II was undiminished by the PKC inhibitor chelerythrine, or by depletion of PKC by prior exposure of cells to PMA for 48 h. Inhibitors of tyrosine kinases, phospholipase C, or mitogen-activated protein kinase kinase also failed to reverse the angiotensin II effect. We conclude that at least two distinct proximal signaling pathways, one involved and one independent of phorbol ester-sensitive protein kinase C, lead to downregulation of NPR-C gene expression by destabilizing its mRNA.
authors.affiliation: Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, 130021, China.
authors.forename: Yuhang
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, 130021, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D017461:Receptors, Atrial Natriuretic Factor / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D000804:Angiotensin II; D011493:Protein Kinase C; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C
keywords: angiotensin II receptor; losartan; natriuretic peptide clearance receptor; phorbol esters; protein kinase C