Abstract-Angiotensin II (Ang II), a circulating hormone that can be synthesized locally in the vasculature, has been implicated in diabetes-associated vascular complications. This study was conducted to determine whether high glucose (HG) (Ϸ23.1 mmol/L), a diabetic-like condition, stimulates Ang II generation and the underlying mechanism of its production in rat vascular smooth muscle cells. The contribution of various enzymes involved in Ang II generation was investigated by silencing their expression with small interfering RNA in cells exposed to normal glucose (Ϸ4.1 mmol/L) and HG. Angiotensin I (Ang I) was generated from angiotensinogen by cathepsin D in the presence of normal glucose or HG. Although HG did not affect the rate of angiotensinogen conversion, it decreased expression of angiotensinconverting enzyme (ACE), downregulated ACE-dependent Ang II generation, and upregulated rat vascular chymasedependent Ang II generation. The ACE inhibitor captopril reduced Ang II levels in the media by 90% in the presence of normal glucose and 19% in HG, whereas rat vascular chymase silencing reduced Ang II production in cells exposed to HG but not normal glucose. The glucose transporter inhibitor cytochalasin B, the aldose reductase inhibitor alrestatin, and the advanced glycation end product formation inhibitor aminoguanidine attenuated HG-induced Ang II generation. HG caused a transient increase in extracellular signal-regulated kinase (ERK)1/2 phosphorylation, and ERK1/2 inhibitors reduced Ang II accumulation by HG. These data suggest that polyol pathway metabolites and AGE can stimulate rat vascular chymase activity via ERK1/2 activation and increase Ang II production. In addition, decreased Ang II degradation, which, in part, could be attributable to a decrease in angiotensin-converting enzyme 2 expression observed in HG, contributes to increased accumulation of Ang II in vascular smooth muscle cells by HG. (Circ Res. 2007;101:455-464.)Key Words: ACE Ⅲ vascular chymase Ⅲ angiotensin Ⅲ VSMC Ⅲ high glucose A ngiotensin (Ang) II, a biologically active component of the renin-angiotensin system (RAS), plays an important role in regulating salt, water, and vascular homeostasis. 1 According to the classical view of RAS, Ang II is cleaved from angiotensin I (Ang I) by angiotensin-converting enzyme (ACE), 2 which is localized on the surface of endothelial cells but also has been shown to be present in the media of aorta and to a lesser degree in adventitia. 3 A soluble form of ACE can be found in plasma. 4 Ang I is formed from the circulating precursor angiotensinogen (AGT) secreted from the liver and is cleaved by renin secreted from the juxtaglomerular cells of the kidney. 5 The presence of local RAS has also been demonstrated in several tissues including vascular wall. 6 AGT is the only known precursor of Ang I and Ang II and is synthesized in vascular smooth muscle cells (VSMCs). 7 Evidence for the presence of renin in vascular tissue has been documented, 8 but renin-like activity in aortic tissue falls to very low ...
Abstract-Cytochrome P450 1B1, expressed in vascular smooth muscle cells, can metabolize arachidonic acid in vitro into several products including 12-and 20-hydroxyeicosatetraenoic acids that stimulate vascular smooth muscle cell growth. This study was conducted to determine whether cytochrome P450 1B1 contributes to angiotensin II-induced rat aortic smooth muscle cell migration, proliferation, and protein synthesis. Angiotensin II stimulated migration of these cells, measured by the wound healing approach, by 1. Metabolism of arachidonic acid to 5-, 12-, 15-, and 20-hydoxyeicosatetraenoic acids in these cells was not altered, but angiotensin II-and arachidonic acid-induced reactive oxygen species production and extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase activity were inhibited by 2,4,3Ј,5Ј-tetramethoxystilbene and cytochrome P450 1B1 small hairpin RNA (shRNA) and by Tempol, which inactivates reactive oxygen species. Tempol did not alter cytochrome P450 1B1 activity. These data suggest that angiotensin II-induced vascular smooth muscle cell migration and growth are mediated by reactive oxygen species generated from arachidonic acid by cytochrome P450 1B1 and activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase. (Hypertension. 2010;55:1461-1467.) Key Words: angiotensin II Ⅲ CYP1B1 Ⅲ vascular smooth muscle cell growth Ⅲ ROS T he renin-angiotensin system is one of the major components of the mechanisms that contribute to the regulation of blood volume and vascular resistance. 1 Angiotensin II (Ang II), the main biologically active agent of this system, also stimulates vascular smooth muscle cell (VSMC) hypertrophy and/or hyperplasia and inflammation and contributes to the development of hypertension, atherosclerosis, heart failure, and restenosis after vascular injury. [1][2][3][4][5][6] The pathophysiological actions of Ang II are mediated by activation of Ն1 serine-threonine and tyrosine kinase, generation of oxygen radicals, 7-9 and/or release of arachidonic acid (AA) by cytosolic phospholipase A 2 (cPLA 2 ) and production of its metabolites, 12-hydroxyeicosatetraenoic acid (12-HETE) and 20-HETE, generated via lipoxygenase and/or cytochrome P450 (CYP) 4A, respectively. 10 -18 Both 12-and 20-HETE promote VSMC migration, hyperplasia, and/or hypertrophy. 11,19 -22 CYP enzymes that metabolize xenobiotics, including polycyclic aromatic hydrocarbons and endobiotics, such as fatty acids and retinoids, are also expressed in extrahepatic tissues, including the cardiovascular system. 23-27 CYP1A1-encoded enzymes are expressed in vascular endothelium and smooth muscle cells, with much higher levels of activity in endothelial cells, whereas CYP1B1 is highly expressed in VSMCs and, to a lesser degree, in endothelial cells, 28,29 but shear stress upregulates mRNA and protein levels of CYP1A1 and CYP1B1 in endothelial cells. 30 Whether CYP1A1 and CYP1B1 contribute to the vascular function is not known. Recombinant CYP1B1 has been shown to me...
Abstract-Hypertension is the leading cause of cardiovascular diseases, and angiotensin II is one of the major components of the mechanisms that contribute to the development of hypertension. However, the precise mechanisms for the development of hypertension are unknown. Our recent study showing that angiotensin II-induced vascular smooth muscle cell growth depends on cytochrome P450 1B1 led us to investigate its contribution to hypertension caused by this peptide. Angiotensin II was infused via miniosmotic pump into rats (150 ng/kg per minute) or mice (1000 g/kg per day) for 13 days resulting in increased blood pressure, increased cardiac and vascular hypertrophy, increased vascular reactivity to vasoconstrictor agents, increased vascular reactive oxygen species production, and endothelial dysfunction in both species. The increase in blood pressure and associated pathophysiological changes were minimized by the cytochrome P450 1B1 inhibitor 2,3Ј,4,5Ј-tetramethoxystilbene in both species and was markedly reduced in Cyp1b1 Ϫ/Ϫ mice. These data suggest that cytochrome P450 1B1 contributes to angiotensin II-induced hypertension and associated pathophysiological changes. Moreover, 2,3Ј,4,5Ј-tetramethoxystilbene, which prevents both cytochrome P450 1B1-dependent and -independent components of angiotensin II-induced hypertension and inhibits associated pathophysiological changes could be clinically useful in the treatment of hypertension and associated cardiovascular and inflammatory diseases. (Hypertension. 2010;56:667-674.) Key Words: angiotensin II Ⅲ cytochrome P450 1B1 Ⅲ Cyp1b1 Ϫ/Ϫ mice Ⅲ blood pressure Ⅲ cardiac and vascular hypertrophy Ⅲ vascular reactivity Ⅲ endothelial function A ngiotensin II (Ang II) is a major component of the mechanisms regulating cardiovascular homeostasis by maintaining vascular tone and salt and water balance. 1 Ang II also activates cytosolic phospholipase A 2 and releases arachidonic acid (AA) from phospholipids. 2 AA is metabolized by cyclooxygenase into prostaglandins and thromboxane A 2 , by lipoxygenase into 5-, 12-, and 15-hydroxyeicosatetraenoic acids (HETEs), by cytochrome P450 (CYP) -hydroxylase into 20-HETE, and by epoxygenase into epoxyeicosatrienoic acids. 3 Prostaglandins E 2 and I 2 and epoxyeicosatrienoic acids contribute to antihypertensive mechanisms, 4,5 whereas prostaglandin precursor PGH 2 and 20-HETE contribute to prohypertensive mechanisms. 6 -8 The balance between these antihypertensive and prohypertensive eicosanoids, together with other vasoactive agents, determines blood pressure levels. Products of AA generated via lipoxygenase (12-HETE) or CYP 4A (20-HETE) also promote vascular smooth muscle cell (VSMC) migration, proliferation, or hypertrophy by activating extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (MAPK) 9 -13 and contribute to the vasoconstrictor action of Ang II. 14 Moreover, inhibitors of lipoxygenase and CYP 4A minimize Ang II-dependent hypertension. 6,15,16 Ang II and AA also stimulate production of reac...
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