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Apelin protects against angiotensin II-induced cardiovascular fibrosis and decreases plasminogen activator inhibitor type-1 production.

ABSTRACT: To test the hypothesis that apelin protects against angiotensin II (Ang II)-induced cardiovascular fibrosis and vascular remodeling.Wild-type mice administered apelin or apelin along with Ang II exhibited less cardiovascular fibrosis and decreased plasminogen activator inhibitor type-1 (PAI-1) gene expression than mice receiving Ang II, N-nitro-L-arginine methyl ester (L-NAME), apelin plus L-NAME or apelin plus Ang II plus L-NAME. In-vitro analysis using a luciferase construct driven by 3.1 kb of the human PAI-1 promoter revealed that apelin blocked Ang II-mediated PAI-1 gene expression. Immunoblotting for phosphorylated myosin phosphatase subunit and myosin light chain revealed that apelin blocked Ang II activation of the Rho kinase pathway, which is associated with induction of PAI-1 gene expression by Ang II. In addition, treatment of human aortic smooth muscle cells with apelin reduced PAI-1 mRNA and protein production in the presence and absence of Ang II. Conversely, L-NAME treatment attenuated the downregulation of PAI-1 by apelin in cells.Apelin protects against cardiac fibrosis and vascular remodeling through direct regulation of PAI-1 gene expression. This protective effect is mediated through the synergistic inhibition of Ang II signaling and increased production of nitric oxide by apelin. Our data extend previous findings and provide new insight into the molecular mechanisms by which apelin elicits a cardioprotective effect.

SUBMITTER: Siddiquee K

PROVIDER: S-EPMC3982221 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Apelin protects against angiotensin II-induced cardiovascular fibrosis and decreases plasminogen activator inhibitor type-1 production.

Siddiquee Khandaker K Hampton Jessica J Khan Susan S Zadory Dan D Gleaves Linda L Vaughan Douglas E DE Smith Layton H LH

Journal of hypertension 20110401 4

<h4>Objective</h4>To test the hypothesis that apelin protects against angiotensin II (Ang II)-induced cardiovascular fibrosis and vascular remodeling.<h4>Methods and results</h4>Wild-type mice administered apelin or apelin along with Ang II exhibited less cardiovascular fibrosis and decreased plasminogen activator inhibitor type-1 (PAI-1) gene expression than mice receiving Ang II, N-nitro-L-arginine methyl ester (L-NAME), apelin plus L-NAME or apelin plus Ang II plus L-NAME. In-vitro analysis u ...[more]

PMID: 21358420

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Project description:Fibrosis is the pathological consequence of stress-induced tissue remodeling and matrix accumulation. Increased levels of plasminogen activator inhibitor type I (PAI-1) have been shown to promote fibrosis in multiple organ systems. Paradoxically, homozygous genetic deficiency of PAI-1 is associated with spontaneous age-dependent, cardiac-selective fibrosis in mice. We have identified a novel PAI-1-dependent mechanism that regulates cardiomyocyte-derived fibrogenic signals and cardiac transcriptional pathways during injury.Cardiac fibrosis in subjects with homozygous mutation in SERPINE-1 was evaluated with late gadolinium-enhanced cardiac magnetic resonance imaging. A murine cardiac injury model was performed by subcutaneous infusion of either saline or Angiotensin II by osmotic minipumps. We evaluated blood pressure, cardiac function (by echocardiography), fibrosis (with Masson Trichrome staining), and apoptosis (with TUNEL staining), and we performed transcriptome analysis (with RNA sequencing). We further evaluated fibrotic signaling in isolated murine primary ventricular myocytes.Cardiac fibrosis was detected in 2 otherwise healthy humans with complete PAI-1 deficiency because of a homozygous frameshift mutation in SERPINE-1. In addition to its suppressive role during spontaneous cardiac fibrosis in multiple species, we hypothesized that PAI-1 also regulates fibrosis during cardiac injury. Treatment of young PAI-1-/- mice with Angiotensin II induced extensive hypertrophy and fibrotic cardiomyopathy, with increased cardiac apoptosis and both reactive and replacement fibrosis. Although Angiotensin II-induced hypertension was blunted in PAI-1-/- mice, cardiac hypertrophy was accelerated. Furthermore, ventricular myocytes were found to be an important source of cardiac transforming growth factor-? (TGF-?) and PAI-1 regulated TGF-? synthesis by cardiomyocytes in vitro as well as in vivo during cardiac injury. Transcriptome analysis of ventricular RNA after Angiotensin II treatment confirmed that PAI-1 deficiency significantly enhanced multiple TGF-? signaling elements and transcriptional targets, including genes for extracellular matrix components, mediators of extracellular matrix remodeling, matricellular proteins, and cardiac integrins compared with wild-type mice.PAI-1 is an essential repressor of cardiac fibrosis in mammals. We define a novel cardiomyocyte-specific regulatory mechanism for TGF-? production by PAI-1, which explains the paradoxical effect of PAI-1 deficiency in promoting cardiac-selective fibrosis. Thus, PAI-1 is a molecular switch that controls the cardiac TGF-? axis and its early transcriptional effects that lead to myocardial fibrosis.

Project description:ObjectivePlasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor that promotes and inhibits cell migration, plays a complex and important role in adverse vascular remodeling. Little is known about the effects of pharmacological PAI-1 inhibitors, an emerging drug class, on migration of vascular smooth muscle cells (SMCs) and endothelial cells (ECs), crucial mediators of vascular remodeling. We investigated the effects of PAI-039 (tiplaxtinin), a specific PAI-1 inhibitor, on SMC and EC migration in vitro and vascular remodeling in vivo.Approach and resultsPAI-039 inhibited SMC migration through collagen gels, including those supplemented with vitronectin and other extracellular matrix proteins, but did not inhibit migration of PAI-1-deficient SMCs, suggesting that its antimigratory effects were PAI-1-specific and physiologically relevant. However, PAI-039 did not inhibit EC migration. PAI-039 inhibited phosphorylation and nuclear translocation of signal transducers and activators of transcription-1 in SMCs, but had no discernable effect on signal transducer and activator of transcription-1 signaling in ECs. Expression of low-density lipoprotein receptor-related protein 1, a motogenic PAI-1 receptor that activates Janus kinase/signal transducers and activators of transcription-1 signaling, was markedly lower in ECs than in SMCs. Notably, PAI-039 significantly inhibited intimal hyperplasia and inflammation in murine models of adverse vascular remodeling, but did not adversely affect re-endothelialization after endothelium-denuding mechanical vascular injury.ConclusionsPAI-039 inhibits SMC migration and intimal hyperplasia, while having no inhibitory effect on ECs, which seems to be because of differences in PAI-1-dependent low-density lipoprotein receptor-related protein 1/Janus kinase/signal transducer and activator of transcription-1 signaling between SMCs and ECs. These findings suggest that PAI-1 may be an important therapeutic target in obstructive vascular diseases characterized by neointimal hyperplasia.

Dataset Information

Apelin protects against angiotensin II-induced cardiovascular fibrosis and decreases plasminogen activator inhibitor type-1 production.

Publications

Apelin protects against angiotensin II-induced cardiovascular fibrosis and decreases plasminogen activator inhibitor type-1 production.

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