International Journal of Cardiology 181 (2015) 355–356

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Letter to the Editor

Interferon regulatory factors: New targets for intervention of cardiovascular diseases Bo He, Zhibing Lu, Hong Jiang ⁎ Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China Cardiovascular Research Institute of Wuhan University, PR China

a r t i c l e

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Article history: Received 16 December 2014 Accepted 21 December 2014 Available online 23 December 2014 Keywords: Interferon regulatory factor Inflammation Cardiac remodeling Cardiovascular disease

The interferon regulatory factor (IRF) family is a group of transcription factors that regulate the expression of interferons and interferonstimulated genes. It has been shown that there are nine members of IRF in mammals [1]. Recently, more and more evidence demonstrate the critical role of IRFs in the regulations of immune responses and immune cell development [1]. As inflammation has been known to be involved in many cardiovascular diseases, the impact of IRFs on immunity highlights the potential therapeutic role of IRF intervention in cardiovascular diseases. It is well known that inflammation and immune response play an important role in the development and progression of atherosclerosis [2]. T lymphocytes have been shown to exert proatherogenic plaque destabilizing influences [3] and T helper cell (Th)1/Th2 functional imbalance, especially enhanced Th1 activity, was observed both in stable coronary artery disease and acute myocardial infarction [4–7]. Pharmacologic blockade of the Th1 pathway or a knockout targeted to the distinct cytokine, interferon-γ, secreted by Th1 cell, can inhibit the development of atherosclerosis [8,9]. Recent evidence indicated that IRFs promote Th1 response and Th1 cell differentiation [1,10]. IRF-1, IRF-2 and IRF-8 have been shown to exert the promotion of either a Th1 response or Th1 cell differentiation of CD4 + T cells through affecting the expression of interleukin-4, interleukin-12 and interleukin-23 [1, 10,11]. Thus, inhibiting the Th1 response and Th1 cell differentiation

⁎ Corresponding author at: Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan 430060, PR China. E-mail address: [email protected] (H. Jiang).

http://dx.doi.org/10.1016/j.ijcard.2014.12.084 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

via the intervention of the corresponding IRFs may be a promising strategy for the prevention of coronary artery disease. Recently, Zhang et al. [12] revealed in mice that IRF-9 gain-of-function promoted the proliferation and migration of vascular smooth muscle cells in response to injury while IRF-9 ablation inhibited the process and attenuated intimal thickening. Huang et al. [13] found that IRF-7 transgenic mice displayed reduced neointima formation and vascular smooth muscle cell proliferation in response to carotid injury, whereas a global knockout of IRF-7 resulted in the opposite effect. In addition, IRF-9 was also shown to be a key mediator of heart dysfunction and cell death following myocardial ischemia/reperfusion injury [14]. These results indicate that IRF-9 and IRF-7 are novel modulators of neointima formation and vascular smooth muscle cell proliferation, while IRF-9 is also involved in the pathogenesis of myocardial ischemia/reperfusion injury, which may represent promising targets for the intervention of over proliferation of vascular smooth muscle cell or ischemia/reperfusion injury resulting from revascularization therapy of coronary artery disease. Besides coronary artery disease, IRFs are also shown to play a key role in cardiac hypertrophy and remodeling, which was demonstrated by a series of experimental studies from our institute. Jiang et al. found that transgenic mice with cardiac-specific IRF-1 or IRF-4 overexpression promoted pressure overload-induced cardiac hypertrophy, ventricular dilation, fibrosis and dysfunction, whereas IRF-1- or IRF-4deficient (knockout) mice showed a significant attenuation in the hypertrophic response [15,16]. Using the similar transgenic mice model, Jiang et al. further revealed that IRF-3, IRF-7, IRF-8 and IRF-9 protected against pressure overload-induced cardiac hypertrophy [17–20]. They also mechanistically clarified that IRF-1 and IRF-4 exerted their promoting effects by activating the expression of inducible nitric oxide synthase and cAMP response element-binding protein at the transcriptional level, respectively [15,16]. However, the protective IRFs (IRF-3, IRF-7, IRF-8 and IRF-9) exerted their roles via different pathways: IRF-3 by inactivating ERK1/2 signaling, IRF-7 by inhibiting nuclear factor-κB signaling, IRF-8 by inhibiting calcineurin signaling and IRF-9 by targeting myocardin, respectively. These exciting results suggest that IRFs are expected to serve as new therapeutic targets for cardiac remodeling, a common phenomenon and/or mechanism of cardiovascular diseases. Taken together, accumulating evidence demonstrates the important role of IRF family members in the progression of cardiovascular diseases. Interventions targeting IRF family members may be new promising targets for the prevention and therapy of cardiovascular diseases.

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Conflict of interest None. References [1] T. Tamura, H. Yanai, D. Savitsky, T. Taniguchi, The IRF family transcription factors in immunity and oncogenesis, Annu. Rev. Immunol. 26 (2008) 535–584. [2] G.K. Hansson, Inflammation, atherosclerosis, and coronary artery disease, N. Engl. J. Med. 352 (2005) 1685–1695. [3] G. Liuzzo, J.J. Goronzy, H. Yang, S.L. Kopecky, D.R. Holmes, R.L. Frye, et al., Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes, Circulation 101 (2000) 2883–2888. [4] X. Cheng, Y.H. Liao, H. Ge, B. Li, J. Zhang, J. Yuan, et al., Th1/Th2 functional imbalance after acute myocardial infarction: coronary arterial inflammation or myocardial inflammation, J. Clin. Immunol. 25 (2005) 246–253. [5] P. Szodoray, O. Timar, K. Veres, H. Der, E. Szomjak, G. Lakos, et al., Th1/Th2 imbalance, measured by circulating and intracytoplasmic inflammatory cytokinesimmunological alterations in acute coronary syndrome and stable coronary artery disease, Scand. J. Immunol. 64 (2006) 336–344. [6] J.L. Fernandes, R.L. Mamoni, J.L. Orford, C. Garcia, A.P. Selwyn, O.R. Coelho, et al., Increased Th1 activity in patients with coronary artery disease, Cytokine 26 (2004) 131–137. [7] H. Methe, S. Brunner, D. Wiegand, M. Nabauer, J. Koglin, E.R. Edelman, Enhanced Thelper-1 lymphocyte activation patterns in acute coronary syndromes, J. Am. Coll. Cardiol. 45 (2005) 1939–1945. [8] E. Laurat, B. Poirier, E. Tupin, G. Caligiuri, G.K. Hansson, J. Bariéty, et al., In vivo downregulation of T helper cell 1 immune responses reduces atherogenesis in apolipoprotein E-knockout mice, Circulation 104 (2001) 197–202. [9] M. Koga, H. Kai, H. Yasukawa, T. Yamamoto, Y. Kawai, S. Kato, et al., Inhibition of progression and stabilization of plaques by postnatal interferon-gamma function blocking in apoE-knockout mice, Circ. Res. 101 (2007) 348–356.

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Interferon regulatory factors: New targets for intervention of cardiovascular diseases.

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