PPARγ Agonist Beyond Glucose Lowering Effect
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
The nuclear hormone receptor PPARγ is activated by several agonists, including members of the thiazolidinedione group of insulin sensitizers. Pleiotropic beneficial effects of these agonists, independent of their blood glucose-lowering effects, have recently been demonstrated in the vasculature. PPARγ agonists have been shown to lower blood pressure in animals and humans, perhaps by suppressing the renin-angiotensin (Ang)-aldosterone system (RAAS), including the inhibition of Ang II type 1 receptor expression, Ang-II-mediated signaling pathways,and Ang-II-induced adrenal aldosterone synthesis/secretion. PPARγ agonists also inhibit the progression of atherosclerosis in animals and humans, possibly through a pathway involving the suppression of RAAS and the thromboxane A2 system, as well as the protection of endothelial function. Moreover, PPARγ-agonist-mediated renal protection, especially the reduction of albuminuria, has been observed in diabetic nephropathy, including animal models of the disease, and in non-diabetic renal dysfunction. The renal protective activities may reflect, at least in part, the ability of PPARγ agonists to lower blood pressure, protect endothelial function, and cause vasodilation of the glomerular efferent arterioles. Additionally, anti-neoplastic effects of PPARγ agonists have recently been described. Based on the multiple therapeutic actions of PPARγ agonists, they will no doubt lead to novel approaches in the treatment of lifestyle-related and other diseases.
Abstract
The nuclear hormone receptor PPARγ is activated by several agonists, including members of the thiazolidinedione group of insulin sensitizers. Pleiotropic beneficial effects of these agonists, independent of their blood glucose-lowering effects, have recently been demonstrated in the vasculature. PPARγ agonists have been shown to lower blood pressure in animals and humans, perhaps by suppressing the renin-angiotensin (Ang)-aldosterone system (RAAS), including the inhibition of Ang II type 1 receptor expression, Ang-II-mediated signaling pathways,and Ang-II-induced adrenal aldosterone synthesis/secretion. PPARγ agonists also inhibit the progression of atherosclerosis in animals and humans, possibly through a pathway involving the suppression of RAAS and the thromboxane A2 system, as well as the protection of endothelial function. Moreover, PPARγ-agonist-mediated renal protection, especially the reduction of albuminuria, has been observed in diabetic nephropathy, including animal models of the disease, and in non-diabetic renal dysfunction. The renal protective activities may reflect, at least in part, the ability of PPARγ agonists to lower blood pressure, protect endothelial function, and cause vasodilation of the glomerular efferent arterioles. Additionally, anti-neoplastic effects of PPARγ agonists have recently been described. Based on the multiple therapeutic actions of PPARγ agonists, they will no doubt lead to novel approaches in the treatment of lifestyle-related and other diseases.
참고문헌 (44)
- Kliewer SA, "Peroxisome proliferator- activated receptors: from genes to physiology", Recent Prog Horm Res, 56, pp.239~263 (2001)
- Marchesi C, "Peroxisome proliferator-activated receptors and the vascular system: beyond their metabolic effects", J Am Soc Hypertens, 2, pp.227~238 (2008)
- Sugawara A, "Effects of PPARγ on hypertension, atherosclerosis, and chronic kidney disease", Endocr J, 57, pp.847~852 (2010)
- Sarafidis PA, "Actions of peroxisome proliferatoractivated receptors-gamma agonists explaining a possible blood pressure-lowering effect", Am J Hypertens, 19, pp.646~653 (2006)
- Dormandy JA, "Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomized controlled trial", Lancet, 366, pp.1279~1289 (2005)
- Sugawara A, "Transcriptional suppression of type 1 angiotensin II receptor gene expression by peroxisome proliferator-activated receptor-gamma in vascular smooth muscle cells", Endocrinology, 142, pp.3125~3134 (2001)
- Sugawara A, "Differential effects among thiazolidinediones on the transcription of thromboxane receptor and angiotensin II type 1 receptor genes", Hypertens Res, 24, pp.229~233 (2001)
- Sugawara A, "Effects of mitogen-activated protein kinase pathway and co-activator CREP-binding protein on peroxisome proliferator-activated receptor-gamma-mediated transcription suppression of angiotensin II type 1 receptor gene", Hypertens Res, 26, pp.623~628 (2003)
- Diep QN, "Structure, endothelial function, cell growth, and inflammation in blood vessels of angiotensin II-infused rats: role of peroxisome proliferator-activated receptor-gamma", Circulation, 105, pp.2296~2302 (2002)
- Benkirane K, "Peroxisome proliferator- activated receptor gamma regulates angiotensin II-stimulated phosphatidylinositol 3-kinase and mitogen-activated protein kinase in blood vessels in vivo", Hypertension, 47, pp.102~108 (2006)
- Ji Y, "PPARgamma agonist, rosiglitazone, regulates angiotensin II-induced vascular inflammation through the TLR4-dependent signaling pathway", Lab Invest, 89, pp.887~902 (2009)
- Uruno A, "Peroxisome proliferatoractivated receptor-{gamma} suppresses CYP11B2 expression and aldosterone production", J Mol Endocrinol, 46, pp.37~49 (2011)
- Wu L, "Beneficial and deleterious effects of rosiglitazone on hypertension development in spontaneously hypertensive rats", Am J Hypertens, 17, pp.749~756 (2004)
- Iglarz M, "Effect of peroxisome proliferator-activated receptor-alpha and - gamma activators on vascular remodeling in endothelin-dependent hypertension", Arterioscler Thromb Vasc Biol, 23, pp.45~51 (2003)
- Ryan MJ, "PPAR(gamma) agonist rosiglitazone improves vascular function and lowers blood pressure in hypertensive transgenic mice", Hypertension, 43, pp.661~666 (2004)
- Tsai YS, "Hypertension and abnormal fat distribution but not insulin resistance in mice with P465L PPARgamma", J Clin Invest, 114, pp.240~249 (2004)
- Barroso I, "Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension", Nature, 402, pp.880~883 (1999)
- Tsai YS, "Genetic variations in peroxisome proliferator-activated receptor gamma expression affect blood pressure", Proc Natl Acad Sci U S A, 106, pp.19084~19089 (2009)
- Ikeda Y, "Suppression of rat thromboxane synthase gene transcription by peroxisome proliferator- activated receptor gamma in macrophages via an interaction with NRF2", J Biol Chem, 275, pp.33142~33150 (2000)
- Sugawara A, "Transcription suppression of thromboxane receptor gene by peroxisome proliferator-activated receptor-gamma via an interaction with Sp1 in vascular smooth muscle cells", J Biol Chem, 277, pp.9676~9683 (2002)
- Majithiya JB, "Pioglitazone, a PPARgamma agonist, restores endothelial function in aorta of streptozotocin-induced diabetic rats", Cardiovasc Res, 66, pp.150~161 (2005)
- Miike T, "Impairment of endothelium-dependent AChinduced relaxation in aorta of diabetic db", db mice: possible dysfunction of receptor and, Naunyn Schmiedebergs Arch Pharmacol, pp.2008, 377[DOI]
- Martens FM, "Shortterm pioglitazone treatment improves vascular function irrespective of metabolic changes in patients with type 2 diabetes", J Cardiovasc Pharmacol, 46, pp.773~778 (2005)
- Staniloae C, "Pioglitazone improves endothelial function in non-diabetic patients with coronary artery disease", Cardiology, 108, pp.164~169 (2007)
- Beyer AM, "Endothelium-specific interference with peroxisome proliferator activated receptor gamma causes cerebral vascular dysfunction in response to a high-fat diet", Circ Res, 103, pp.654~661 (2008)
- Marx N, "Vascular effects of PPARgamma activators: from bench to bedside", Prog Lipid Res, 46, pp.283~296 (2007)
- Lim S, "PPARgamma gene transfer sustains apoptosis, inhibits vascular smooth muscle cell proliferation, and reduces neointima formation after balloon injury in rats", Arterioscler Thromb Vasc Biol, 26, pp.808~813 (2006)
- Joner M, "Pioglitazone inhibits in-stent restenosis in atherosclerotic rabbits by targeting transforming growth factor-beta and MCP-1", Arterioscler Thromb Vasc Biol, 27, pp.182~189 (2007)
- Webb DR, "Searching for the right outcome? A systematic review and meta-analysis of controlled trials using carotid intima-media thickness or pulse wave velocity to infer antiatherogenic properties of thiazolidinediones", Diabetes Obes Metab, 12, pp.124~132 (2010)
- Kudo M, "Effects of pioglitazone, belaprost, and fluvastatin on gene expression in vascular endothelial cells revealed by DNA microarray analyses", J Hypertens, 24(6), pp.238~ (2006)
- Polikandriotis JA, "Peroxisome proliferator-activated receptor gamma ligands stimulate endothelial nitric oxide production through distinct peroxisome proliferator-activated receptor gamma-dependent mechanisms", Arterioscler Thromb Vasc Biol, 25, pp.1810~1816 (2005)
- Werner C, "The peroxisome proliferator-activated receptor-gamma agonist pioglitazone increases number and function of endothelial progenitor cells in patients with coronary artery disease and normal glucose tolerance", Diabetes, 56, pp.2609~2615 (2007)
- Kleinhenz JM, "Disruption of endothelial peroxisome proliferator-activated receptor-gamma reduces vascular nitric oxide production", Am J Physiol Heart Circ Physiol, 297, pp.1647~1654 (2009)
- Sato K, "Expression of peroxisome proliferator-activated receptor isoform proteins in the rat kidney", Hypertens Res, 27, pp.417~425 (2004)
- 안경옥, "Induction of PPAR Gamma mRNA and Protein Expression by Rosiglitazone in Chronic Cyclosporine Nephropathy in the Rat", Yonsei Medical Journal, 48(2), pp.308~316 (2007), 연세대학교의과대학
- Arima S, "Biphasic vasodilator action of troglitazone on the renal microcirculation", J Am Soc Nephrol, 13, pp.342~349 (2002)
- 차대룡, "Thiazolidinediones expand body fluid volume through PPAR gamma stimulation of ENaC-mediated renal salt absorption", NATURE MEDICINE, 11(8), pp.861~866, NATURE PUBLISHING GROUP
- Yang J, "Role of PPARgamma in renoprotection in type 2 diabetes: molecular mechanisms and therapeutic potential", Clin Sci (Lond), 116, pp.17~26 (2009)
- Sarafidis PA, "Effect of thiazolidinediones on albuminuria and proteinuria in diabetes: a meta-analysis", Am J Kidney Dis, 55, pp.835~847 (2010)
- Chung BH, "Protective effect of peroxisome proliferator activated receptor gamma agonists on diabetic and non-diabetic renal diseases", Nephrology (Carlton), 10, pp.40~43 (2005)
- Chung BH, "Rosiglitazone protects against cyclosporine-induced pancreatic and renal injury in rats", Am J Transplant, 5, pp.1856~1867 (2005)
- Yang HC, "The PPARgamma agonist pioglitazone ameliorates aging-related progressive renal injury", J Am Soc Nephrol, 20, pp.2380~2388 (2009)
- Blanquicett C, "Thiazolidinediones as anticancer agents", Cancer Ther, 6, pp.25~34 (2008)
- Yamauchi A, "Thiazolidinediones inhibit REG Ialpha gene transcription in gastrointestinal cancer cells", Biochem Biophys Res Commun, 379, pp.743~748 (2009)