STAT1 and STAT3 as intracellular regulators of vascular remodeling

Wincewicz, Andrzej; Sulkowska, M; Rutkowski, Ryszard; Sulkowski, Stanisław; Musiatowicz, B; Hirnle, Tomasz; Famulski, W; Koda, Mariusz; Sokol, Grzegorz; Szarejko, Przemyslaw

doi:10.1016/j.ejim.2006.12.007

Cited by 28 publications

(24 citation statements)

References 30 publications

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“…41 Induction of STAT proteins was traditionally associated with inflammatory response. 25,42 Their overexpression can affect the regulation of ischemic cardiac damage during hypoxia.…”

Section: Resultsmentioning

confidence: 99%

Stat Proteins as Intracellular Regulators of Resistance to Myocardial Injury in Context of Cardiac Remodeling and Targeting for Therapy

Wincewicz¹,

Sulkowski²

2017

Adv Clin Exp Med

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The roles of STAT (signal transducers and activators of transcription) proteins are widely discussed in relation to other agents like IFN-γ that are involved in cardiovascular diseases. STAT3 protects cardiomyocytes during endotoxic shock and ischemia and prolongs survival of these cells by activation of antiapoptotic genes like Bcl-2 and c-Fos. Moreover, IL-6 dependent expression of STAT3 is probably responsible for hypertrophy of cardiomyocytes. On the contrary, STAT1 mediates cell death by induction of caspase-1. STAT6 probably enhances cellular damage in myocardial infraction, which is significantly reduced in mice with the knockout STAT6 gene. Considering these facts, we attempted to review in this paper the role of STAT proteins in myocardial remodeling, highlighting STAT3 as a potent mediator of cardioprotection. Our review also aims to acquaint a broad audience of internal medicine practitioners with the STAT3-related molecular mechanisms that underlie the therapeutic properties of such widely administered drugs as angiotensin II type 1 (AT1) receptor antagonists and HMG-CoA reductase inhibitors, such as losartan and lovastatin.

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“…41 Induction of STAT proteins was traditionally associated with inflammatory response. 25,42 Their overexpression can affect the regulation of ischemic cardiac damage during hypoxia.…”

Section: Resultsmentioning

confidence: 99%

Stat Proteins as Intracellular Regulators of Resistance to Myocardial Injury in Context of Cardiac Remodeling and Targeting for Therapy

Wincewicz¹,

Sulkowski²

2017

Adv Clin Exp Med

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“…STAT1 is known to antagonize the functions of STAT3 in multiple biological processes including differentiation, apoptosis and vascular formation [19,42,43]. IFNc, a pluripotent cytokine, predominantly activates STAT1 but weakly activates STAT3.…”

Section: Discussionmentioning

confidence: 99%

“…The activation of STAT1 is required for inhibiting endothelial cell growth and tube formation induced by interferon gamma (IFN-c). Moreover, STAT1-deficient mice have increased angiogenic responses in the Matrigel plug assay, suggesting that STAT1 is a prominent negative regulator of angiogenesis [19]. STAT1 is also essential for IFN-bmediated inhibition of bFGF production, indicating that STAT1 is an important mediator for anti-angiogenic signals like IFN [20].…”

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confidence: 99%

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STAT1 activation by venous malformations mutant Tie2-R849W antagonizes VEGF-A-mediated angiogenic response partly via reduced bFGF production

Huang

Pan

et al. 2012

Angiogenesis

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A missense mutation from arginine to tryptophan at residue 849 in the kinase domain of Tie2 (Tie2-R849W) is commonly identified in familial venous malformations. The mechanistic action of Tie2-R849W variant expression on angiogenic cascades including smooth muscle cell recruitment, however, remains elusive. To avoid confounding factors from endogenous Tie2 expression, Tie2-depleted endothelial cells (ECs) were used to study the effects of ectopic shRNA-resistant Tie2 variant expression, Tie2-WT* and Tie2-R849W*, on vascular cell proliferation, migration, tube formation, and smooth muscle cell (SMC) recruitment. Tie2-R849W* induced STAT1 phosphorylation at Tyr701. Tie2-R849W*-expressing cells had reduced ability to migrate and form tubes on Matrigel than their wildtype counterparts. STAT1 phosphorylation attenuated VEGF-A-induced STAT3 tyrosine phosphorylation in Tie2-R849W*-expressing HUVECs. The induced STAT1 activation also decreased VEGF-A-induced bFGF mRNA expression by competing with activated STAT3 for a direct binding to the consensus STAT-binding site at positions -997 to -989 bp from transcription start site in the bFGF promoter. Depleting STAT1 expression rescued the inability of Tie2-R849W expression to mediate angiogenesis. Moreover, bFGF neutralization or constitutive STAT1 activation, reminiscence of Tie2-R849W* expression, suppressed the smooth muscle cell recruiting ability of endothelial conditioned medium. This work reveals an anti-angiogenic role of STAT1 activation that acts in Tie2-R849W-expressing ECs to impair VEGF-A-mediated STAT3 signaling, bFGF production, and smooth muscle cell recruitment. A balancing activity of STAT1 and STAT3 may be important for Tie2-mediated vascular homeostasis.

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“…Thus far, seven members of this protein family have been discovered: STAT1, 2, 3, 4, 5a, 5b, and 6. All STAT proteins share high sequence homology, but are expressed differentially (43). STATs 2, 4, and 6 are activated specifically by a small subset of cytokines (IFNa/IL-6, 12, and 13, respectively).…”

Section: Introductionmentioning

confidence: 99%

Expression and Activation of STAT Family Proteins in Cerebral Arteriovenous Malformations

et al. 2012

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STAT1 and STAT3 as intracellular regulators of vascular remodeling

Cited by 28 publications

References 30 publications

Stat Proteins as Intracellular Regulators of Resistance to Myocardial Injury in Context of Cardiac Remodeling and Targeting for Therapy

Stat Proteins as Intracellular Regulators of Resistance to Myocardial Injury in Context of Cardiac Remodeling and Targeting for Therapy

STAT1 activation by venous malformations mutant Tie2-R849W antagonizes VEGF-A-mediated angiogenic response partly via reduced bFGF production

Expression and Activation of STAT Family Proteins in Cerebral Arteriovenous Malformations

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