title: Angiotensin II enhances integrin and alpha-actinin expression in adult rat cardiac fibroblasts.
abstract: Angiotensin II (Ang II) plays an important role in cardiac remodeling through stimulation of proliferation and extracellular matrix (ECM) production in cardiac fibroblasts. Integrins are a family of transmembrane receptors that mediate the attachment of cells to ECM. We hypothesized that Ang II regulation of integrins further contributes to its role in cardiac remodeling. We cultured adult rat cardiac fibroblasts with and without Ang II (100 nmol/L) to determine the effects on mRNA and protein levels of integrins, as well as alpha-actinin and other cytoskeletal proteins that link to integrins at the site of focal adhesions. Ang II was also added in the presence of irbesartan (10 micromol/L), a specific Ang II type 1 (AT(1)) receptor antagonist, or PD 123319 (10 micromol/L), a specific Ang II type 2 receptor antagonist. To investigate the function of these integrins, we determined the effects of blocking antibodies on Ang II-induced adhesion to ECM. We also treated spontaneously hypertensive rats (SHR) with an AT(1) receptor blocker, losartan, or with hydralazine to investigate integrin and alpha-actinin expression in treated and untreated SHR. Ang II enhanced alpha(v), beta(1), beta(3), and beta(5) integrins; osteopontin; and alpha-actinin mRNA and protein levels in cardiac fibroblasts. All of these effects were inhibited by irbesartan but not by PD 123319. Pretreatment of cardiac fibroblasts with Ang II enhanced cell attachment to ECM proteins and induced focal adhesion kinase phosphorylation. Blocking antibodies to beta(3) and alpha(v)beta(5) attenuated Ang II-induced adhesion. In SHR, ventricular alpha(v) and beta(5) integrin expression and alpha-actinin were increased compared with those in Wistar-Kyoto rats. Although both losartan and hydralazine lowered mean arterial pressure and decreased peripheral vascular resistance, only losartan attenuated the increased integrin, alpha-actinin, fibronectin laminin, and osteopontin expression and the increased left ventricular mass (as determined with echocardiography). Hydralzine had none of these effects. Although both agents attenuated beta-myosin heavy chain expression, a marker of hypertrophy, losartan had a greater effect. These results suggest that integrins and alpha-actinin are upregulated by Ang II and in left ventricular hypertrophy and that the block of expression of these proteins through inhibition of the AT(1) receptor is associated with attenuation of the hypertrophic response. Ang II induces integrin and alpha-actinin expression in cardiac fibroblasts that is associated with adhesion and left ventricular hypertrophy and blocked through inhibition of the AT(1) receptor.
authors.affiliation: Department of Medicine, Division of Endocrinology, University of California at Los Angeles School of Medicine, 90024, USA.
authors.forename: H
authors.initials: H
authors.lastname: Kawano
authors.forename: R J
authors.initials: RJ
authors.lastname: Cody
authors.forename: K
authors.initials: K
authors.lastname: Graf
authors.forename: S
authors.initials: S
authors.lastname: Goetze
authors.forename: Y
authors.initials: Y
authors.lastname: Kawano
authors.forename: J
authors.initials: J
authors.lastname: Schnee
authors.forename: R E
authors.initials: RE
authors.lastname: Law
authors.forename: W A
authors.initials: WA
authors.lastname: Hsueh
mesh_terms: D000185:Actinin / Q000235:genetics*; D000367:Age Factors; D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D006332:Cardiomegaly / Q000503:physiopathology; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D005353:Fibronectins / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D006830:Hydralazine / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D039564:Integrin alphaV; D039641:Integrin beta Chains; D019012:Integrin beta1 / Q000235:genetics; D039661:Integrin beta3; D016023:Integrins / Q000235:genetics*; D000077405:Irbesartan; D007797:Laminin / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D009206:Myocardium / Q000737:chemistry* / Q000166:cytology*; D010766:Phosphorylation; D010980:Platelet Membrane Glycoproteins / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D019096:Vitronectin / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; D015703:Antigens, CD; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D015815:Cell Adhesion Molecules; D005353:Fibronectins; D007093:Imidazoles; D039564:Integrin alphaV; D039641:Integrin beta Chains; D019012:Integrin beta1; D039661:Integrin beta3; D016023:Integrins; D007797:Laminin; D010980:Platelet Membrane Glycoproteins; D011725:Pyridines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D019096:Vitronectin; C084344:integrin beta5; D000185:Actinin; D000804:Angiotensin II; C073402:PD 123319; D006830:Hydralazine; D003094:Collagen; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496052:Ptk2 protein, rat; D000077405:Irbesartan; D019808:Losartan