Many recent reports provide strong evidence that MCP- 1 plays a major role in the development of ischemic heart disease (IHD) that is responsible for the majority of the 5 million human heart failure cases in the US, but the underlying mechanism is not known. We postulate that MCP-1-induced gene expression changes in the monocytes and the consequent production of cytokines and other biologically active molecules, as well as possible direct effects of MCP- 1 on the major cell types in the myocardium can lead to the development of IHD. IHD probably develops as a net consequence of the interplay of these events which involve many cell types and many biologically active molecules. Therefore in vitro studies on isolated cells cannot accurately reflect the interactions involved in IND. On the other hand a genomic approach can discover the genes whose altered expression in the heart leads to the development of IHD. Such an approach, although not possible on humans, can be done on a suitable animal model. We have developed a transgenic murine model that faithfully recapitulates most features of human IRD. Use of this model has a high likelihood of discovering novel genes as illustrated by our discovery of a previously unknown MCP-1-induced protein (MCPIP). With this overall objective we propose to pursue the following specific aims: 1.) Identify gene expression changes that occur in the ventricle during IHD development induced by targeted expression of MCP 1 in the CMC of transgenic mice using gene chip technology. 2.) Determine the function of the novel MCPIP: a) Determine whether a) MCPIP expression causes cell death, b) this death is enhanced by MCP-l and its receptor CCR2, c) whether the cell death shares features characteristic of apoptosis, d) MCPIP has a transcription factor-like activity and whether structural features required for this activity are also required for the cell death-inducing activity. 3.) Assess the role of apoptosis in the development of MCP 1-induced cardiovascular disease by testing whether a) prevention of monocyte apoptosis by targeted expression of Bc12 or b) prevention of apoptosis by absence of Fas or expression of sFas in the myocytes would delay or rescue the development of the disease. The approach proposed here will identify MCP-l induced alterations in the expression of known genes not previously implicated in IHD and novel genes of unknown function that are involved in IHD. These genes are likely to reveal novel targets for intervention in IND and genes with prognostic value.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Pathology A Study Section (PTHA)
Program Officer
Massicot-Fisher, Judith
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Schools of Medicine
United States
Zip Code
Jin, Zhuqing; Liang, Jian; Wang, Jing et al. (2015) MCP-induced protein 1 mediates the minocycline-induced neuroprotection against cerebral ischemia/reperfusion injury in vitro and in vivo. J Neuroinflammation 12:39
Kapoor, Nidhi; Niu, Jianli; Saad, Yasser et al. (2015) Transcription factors STAT6 and KLF4 implement macrophage polarization via the dual catalytic powers of MCPIP. J Immunol 194:6011-23
Niu, Jianli; Jin, Zhuqing; Kim, Hyunbae et al. (2015) MCP-1-induced protein attenuates post-infarct cardiac remodeling and dysfunction through mitigating NF-?B activation and suppressing inflammation-associated microRNA expression. Basic Res Cardiol 110:26
Garg, Abhishek V; Amatya, Nilesh; Chen, Kong et al. (2015) MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation. Immunity 43:475-87
Younce, Craig W; Niu, Jianli; Ayala, Jennifer et al. (2014) Exendin-4 improves cardiac function in mice overexpressing monocyte chemoattractant protein-1 in cardiomyocytes. J Mol Cell Cardiol 76:172-6
Niu, Jianli; Gilliland, M G F; Jin, Zhuqing et al. (2014) MCP-1and IL-1? expression in the myocardia of two young patients with Type 1 diabetes mellitus and fatal diabetic ketoacidosis. Exp Mol Pathol 96:71-9
Niu, Jianli; Wang, Kangkai; Zhelyabovska, Olga et al. (2013) MCP-1-induced protein promotes endothelial-like and angiogenic properties in human bone marrow monocytic cells. J Pharmacol Exp Ther 347:288-97
Jin, Zhuqing; Liang, Jian; Wang, Jing et al. (2013) Delayed brain ischemia tolerance induced by electroacupuncture pretreatment is mediated via MCP-induced protein 1. J Neuroinflammation 10:63
Roy, Arpita; Zhang, Miaojun; Saad, Yasser et al. (2013) Antidicer RNAse activity of monocyte chemotactic protein-induced protein-1 is critical for inducing angiogenesis. Am J Physiol Cell Physiol 305:C1021-32
Roy, Arpita; Kolattukudy, Pappachan E (2012) Monocyte chemotactic protein-induced protein (MCPIP) promotes inflammatory angiogenesis via sequential induction of oxidative stress, endoplasmic reticulum stress and autophagy. Cell Signal 24:2123-31

Showing the most recent 10 out of 34 publications