Angiogenesis, the formation of new blood vessels from preexisting vessels in adult tissue, is a key process involved in inflammatory diseases such as diabetes, ischemic heart, and limb diseases and tumor growth (1, 2). Although the critical initiating event for the generation of new blood vessels has been attributed to the production of growth factors, recruitment of monocytes has been suggested to be important in the angiogenic cascade (3, 4). Accumulation of leukocytes at the inflammatory sites is regulated by chemotactic small molecular weight proteins called chemokines. Monocyte chemotactic protein-1 (MCP-1), 2 a key CC chemokine responsible for trafficking and activation of monocytes/macrophages through its receptor CCR2, has been implicated in inflammation and angiogenesis (5, 6). Administration of exogenous MCP-1 has been shown to increase monocyte/macrophage recruitment, collateral vessel formation, and blood flow to the ischemic tissue in hindlimb models of ischemia (6 -8). By drilling tunnels through myocardial tissue, monocytes/macrophages were reported to increase angiogenesis in ischemic myocardium (9). MCP-1 can also directly act on endothelial cells (ECs) to induce angiogenesis (10, 11). However, the mechanisms by which MCP-1 mediates these effects on angiogenesis are unclear.We recently identified a novel transcription factor, designated MCP-1-induced protein (MCPIP), which was originally found in human monocytes after treatment with MCP-1 and is proapoptotic (12). MCP-1 induces this transcription factor, which in turn up-regulates members of the apoptotic gene family that have been linked to angiogenesis and vascular remodeling (13-15). Therefore, it appeared possible that MCP-1-induced angiogenesis might be mediated by transcription factor MCPIP. Here, we report that MCP-1 treatment of human umbilical vein endothelial cells (HUVECs) resulted in induction of MCPIP and that expression of MCPIP enhanced endothelial cell apoptosis, proliferation, migration, and expression of angiogenesis-related genes, resulting in capillary-like tube formation. All of these angiogenic effects of MCP-1 and expression of MCPIP were inhibited by MCPIP-specific small interfering RNA (siRNA). The chromatin immunoprecipitation assay revealed that cadherin (cdh)12 and cdh19 were in vivo targets of MCPIP. Knockdown of MCPIP expression significantly reduced transcript levels of cdh12 and cdh19. Moreover, knockdown of either cdh12 or cdh19 expression inhibited MCPIP-induced capillary-like tube formation. These results strongly suggest that MCP-1-induced angiogenesis is mediated via induction of MCPIP, the newly discovered transcription factor, at least in part through transcriptional activation of cdh12 and cdh19 that have not previously been implicated in angiogenesis. EXPERIMENTAL PROCEDURESCell Culture Conditions-The HUVECs (Clonetics) were grown in endothelial cell basal medium supplemented with hydrocortisone (1 g/ml), bovine brain extract (12 g/ml), gen-* This work was supported, in whole or in part, by National Insti...
Rationale: Peroxisome proliferator-activated receptors (PPARs) (␣, ␥, and ␦/) are nuclear hormone receptors and ligand-activated transcription factors that serve as key determinants of myocardial fatty acid metabolism. Long-term cardiomyocyte-restricted PPAR␦ deficiency in mice leads to depressed myocardial fatty acid oxidation, bioenergetics, and premature death with lipotoxic cardiomyopathy. Objective: To explore the essential role of PPAR␦ in the adult heart. Methods and Results: We investigated the consequences of inducible short-term PPAR␦ knockout in the adult mouse heart. In addition to a substantial transcriptional downregulation of lipid metabolic proteins, short-term PPAR␦ knockout in the adult mouse heart attenuated cardiac expression of both Cu/Zn superoxide dismutase and manganese superoxide dismutase, leading to increased oxidative damage to the heart. Moreover, expression of key mitochondrial biogenesis determinants such as PPAR␥ coactivator-1 were substantially decreased in the short-term PPAR␦ deficient heart, concomitant with a decreased mitochondrial DNA copy number. Rates of palmitate and glucose oxidation were markedly depressed in cardiomyocytes of PPAR␦ knockout hearts. Consequently, PPAR␦ deficiency in the adult heart led to depressed cardiac performance and cardiac hypertrophy. Conclusions: PPAR␦ is an essential regulator of cardiac mitochondrial protection and biogenesis and PPAR␦ activation can be a potential therapeutic target for cardiac disorders. (Circ Res. 2010;106:911-919.)
Abstract-Peroxisome proliferator-activated receptor /␦ (PPAR/␦) is an essential transcription factor in myocardial metabolism. This study aims to investigate the effects of PPAR/␦ activation in the adult heart on mitochondrial biology and oxidative metabolism under normal and pressure-overload conditions. We have investigated the effects of cardiac constitutively active PPAR/␦ in adult mice using a tamoxifen-inducible transgenic approach with Cre-LoxP recombination. The expression of PPAR/␦ mRNA and protein in cardiomyocytes of adult mice was substantially increased after short-term induction. In these mice, the cardiac expression of key factors involved in mitochondrial biogenesis, such as PPAR␥ coactivator-1, endogenous antioxidants Cu/Zn superoxide dismutase, and catalase, fatty acid, and glucose metabolism, such as carnitine palmitoyltransferase Ib, carnitine palmitoyltransferase II, and glucose transporter 4, were upregulated. Subsequently, myocardial oxidative metabolism was elevated concomitant with an increased mitochondrial DNA copy number and an enhanced cardiac performance. Moreover, activation of PPAR/␦ in the adult heart improved cardiac function and resisted progression to pathological development in mechanical stress condition. We conclude that PPAR/␦ activation in the adult heart will promote cardiac performance along with transcriptional upregulation of mitochondrial biogenesis and defense, as well as oxidative metabolism at basal and pressure-overload conditions. (Hypertension. 2011;57:223-230.) • Online Data Supplement
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.