Advances in Clinical and Experimental Medicine
2017, vol. 26, nr 4, July, p. 703–708
doi: 10.17219/acem/62693
PubMed ID: 28691428
Publication type: review article
Language: English
Download citation:
Stat proteins as intracellular regulators of resistance to myocardial injury in the context of cardiac remodeling and targeting for therapy
1 Specialist Medical Practice-Pathologist, Non-Public Health Care Unit, Department of Pathology, Kielce, Poland
2 Department of General Pathomorphology, Medical University of Bialystok, Poland
Abstract
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.
Key words
apoptosis, signal transduction, cardiac remodeling, therapeutic implications
References (42)
- Akira S. Functional roles of STAT family proteins: Lessons from knockout mice. Stem Cells. 1999;17:138–146.
- Wang Y, Malabarba MG, Nagy ZS, Kirken RA. Interleukin 4 regulates phosphorylation of serine 756 in the transactivation domain of Stat6. Roles for multiple phosphorylation sites and Stat6 function. J Biol Chem. 2004;279:25196–25203.
- Calo V, Migliavacca M, Bazan V, et al. STAT proteins: From normal control of cellular events to tumorigenesis. J Cell Physiol. 2003;197:157–168.
- Varinou L, Ramsauer K, Karaghiosoff M, et al. Phosphorylation of the Stat1 transactivation domain is required for full-fledged IFN-gamma-dependent innate immunity. Immunity. 2003;19:793–802.
- Bromberg J. Stat proteins and oncogenesis. J Clin Invest. 2002;109:1139–1142.
- Kunisada K, Tone E, Fujio Y, Matsui H, Yamauchi-Takihara K, Kishimoto T. Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytes. Circulation. 1998;98:346–352.
- Funamoto M, Fujio Y, Kunisada K, et al. Signal transducer and activator of transcription 3 is required for glycoprotein 130-mediated induction of vascular endothelial growth factor in cardiac myocytes. J Biol Chem. 2000;275:10561–10566.
- Osugi T, Oshima Y, Fujio Y, et al. Cardiac-specific activation of signal transducer and activator of transcription 3 promotes vascular formation in the heart. J Biol Chem. 2002;277:6676–6681.
- Hilfiker-Kleiner D, Hilfiker A, Fuchs M, et al. Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury. Circ Res. 2004;95:187–195.
- Negoro S, Kunisada K, Fujio Y, et al. Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganese superoxide dismutase. Circulation. 2001;104:979–981.
- Wollert KC, Taga T, Saito M, et al. Cardiotrophin-1 activates a distinct form of cardiac muscle cell hypertrophy. Assembly of sarcomeric units in series VIA gp130/leukemia inhibitory factor receptor-dependent pathways. J Biol Chem. 1996;271:9535–9545.
- Kunisada K, Negoro S, Tone E, et al. Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy. Proc Natl Acad Sci USA. 2000;97:315–319.
- Podewski EK, Hilfiker-Kleiner D, Hilfiker A, et al. Alterations in Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling in patients with end-stage dilated cardiomyopathy. Circulation. 2003;107:798–802.
- Jacoby JJ, Kalinowski A, Liu MG, et al. Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age. Proc Natl Acad Sci USA. 2003;100:12929–12934.
- Sano M, Fukuda K, Kodama H, et al. Autocrine/Paracrine secretion of IL-6 family cytokines causes angiotensin II-induced delayed STAT3 activation. Biochem Biophys Res Commun. 2000;269:798–802.
- Kodama H, Fukuda K, Pan J, et al. Biphasic activation of the JAK/STAT pathway by angiotensin II in rat cardiomyocytes. Circ Res. 1998;82:244–250.
- Booz GW, Day JN, Speth R, Baker KM. Cytokine G-protein signaling crosstalk in cardiomyocytes: Attenuation of Jak-STAT activation by endothelin-1. Mol Cell Biochem. 2002;240:39–46.
- Hattori R, Maulik N, Otani H, et al. Role of STAT3 in ischemic preconditioning. J Mol Cell Cardiol. 2001;33:1929–1936.
- Stephanou A, Brar BK, Scarabelli TM, et al. Ischemia-induced STAT-1 expression and activation play a critical role in cardiomyocyte apoptosis. J Biol Chem. 2000;275:10002–10008.
- Stephanou A, Scarabelli TM, Brar BK, et al. Induction of apoptosis and Fas receptor/Fas ligand expression by ischemia/reperfusion in cardiac myocytes requires serine 727 of the STAT-1 transcription factor but not tyrosine 701. J Biol Chem. 2001;276:28340–28347.
- Fujio Y, Kunisada K, Hirota H, Yamauchi-Takihara K, Kishimoto T. Signals through gp130 upregulate bcl-x gene expression via STAT1-binding cis-element in cardiac myocytes. J Clin Invest. 1997;99:2898–2905.
- Kawai M, Kawashima S, Sakoda T, et al. Ral GDP dissociation stimulator and Ral GTPase are involved in myocardial hypertrophy. Hypertension. 2003;41:956–962.
- Sheng Z, Knowlton K, Chen J, Hoshijima M, Brown JH, Chien KR. Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy. J Biol Chem. 1997;272:5783–5791.
- Yamaura G, Turoczi T, Yamamoto F, Siddqui MA, Maulik N, Das DK. STAT signaling in ischemic heart: A role of STAT5A in ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2003;285:H476–482.
- Oikonomou E1, Tousoulis D, Siasos G, Zaromitidou M, Papavassiliou AG, Stefanadis C. The role of inflammation in heart failure: New therapeutic approaches. Hellenic J Cardiol. 2011;52:30–40.
- Han C, Nie Y, Lian H, Liu R, He F, Huang H, Hu S. Acute inflammation stimulates a regenerative response in the neonatal mouse heart. Cell Res. 2015 Sep 11. doi: 10.1038/cr.2015.110. [Epub ahead of print]
- Zouein FA, Kurdi M, Booz GW. Dancing rhinos in stilettos: The amazing saga of the genomic and nongenomic actions of STAT3 in the heart. JAKSTAT. 2013; 2:e24352.
- Haghikia A, Ricke-Hoch M, Stapel B, Gorst I, Hilfiker-Kleiner D. STAT3, a key regulator of cell-to-cell communication in the heart. Cardiovasc Res. 2014;102:281–289
- Fiaschi T, Magherini F, Gamberi T, et al. Hyperglycemia and angiotensin II cooperate to enhance collagen I deposition by cardiac fibroblasts through a ROS-STAT3-dependent mechanism. Biochim Biophys Acta. 2014;1843:2603–2610.
- Owais K, Huang T, Mahmood F, et al. Cardiopulmonary bypass decreases activation of the Signal Transducer and Activator of Transcription 3 (STAT3) pathway in diabetic human myocardium. Ann Thorac Surg. 2015 pii: S0003-4975(15)00835-8. [Epub ahead of print].
- Enomoto D, Obana M, Miyawaki A, Maeda M, Nakayama H, Fujio Y. Cardiac-specific ablation of the STAT3 gene in the subacute phase of myocardial infarction exacerbated cardiac remodeling. Am J Physiol Heart Circ Physiol. 2015;309:H471–480.
- Zheng LY, Zhang MH, Xue JH, Li Y, Nan Y, Li MJ, Wang J, Du XP. Effect of angiotensin II on STAT3 mediated atrial structural remodeling. Eur Rev Med Pharmacol Sci. 2014;18:2365–2377.
- Ma MC, Wang BW, Yeh TP, et al. Interleukin-27, a novel cytokine induced by ischemia-reperfusion injury in rat hearts, mediates cardioprotective effects via the gp130/STAT3 pathway. Basic Res Cardiol. 2015;110:22.
- McGinnis GR, Ballmann C, Peters B, et al. Interleukin-6 mediates exercise preconditioning against myocardial ischemia reperfusion injury. Am J Physiol Heart Circ Physiol. 2015;308:H1423–1433.
- Heusch G, Musiolik J, Kottenberg E, Peters J, Jakob H, Thielmann M. STAT5 activation and cardioprotection by remote ischemic preconditioning in humans: Short communication. Circ Res. 2012;110:111–115.
- Skyschally A, Gent S, Amanakis G, Schulte C, Kleinbongard P, Heusch G. Across-species transfer of protection by remote ischemic preconditioning with species-specific myocardial signal transduction by reperfusion injury salvage kinase and survival activating factor enhancement pathways. Circ Res. 2015;117:279–288.
- Nural-Guvener H, Zakharova L, Feehery L, Sljukic S, Gaballa M. Anti-fibrotic effects of class I HDAC inhibitor, mocetinostat is associated with IL-6/Stat3 signaling in ischemic heart failure. Int J Mol Sci. 2015;16:11482–11499.
- Wang L, Li J, Li D. Losartan reduces myocardial interstitial fibrosis in diabetic cardiomyopathy rats by inhibiting JAK/STAT signaling pathway. Int J Clin Exp Pathol. 2015;8:466–473.
- Guo W, Liu H, Li L, Yang M, Du A. Regulation of lovastatin on a key inflammation-related microRNA in myocardial cells. Chin Med J (Engl). 2014;127:2977–2981.
- Al-Rasheed NM, Al-Oteibi MM, Al-Manee RZ, et al. Simvastatin prevents isoproterenol-induced cardiac hypertrophy through modulation of the JAK/STAT pathway. Drug Des Devel Ther. 2015;9:3217–3229.
- Wincewicz A, Sulkowska M, Rutkowski R, et al. STAT1 and STAT3 as intracellular regulators of vascular remodeling. Eur J Intern Med. 2007;18:267–271.
- Wincewicz A, Moniuszko T, Sulkowska M, Rutkowski R, Koda M, Sulkowski S. Involvement of STAT proteins in the pathogenesis of autoimmune diseases. Adv Clin Exp Med. 2005;14:785–790.