A Mechanism Underlying Hypertensive Occurrence in the Metabolic Syndrome: Cooperative Effect of Oxidative Stress and Calcium Accumulation in Vascular Smooth Muscle Cells

Abstract

Several lines of evidence indicate that reactive oxygen species (ROS) overproduction under the metabolic syndrome condition is the leading cause of cardiovascular events. Calcium is an important stimulus for vasoconstriction and plays a pivotal role in the development of hypertension. Here, we investigate whether a relationship exists between metabolic syndrome-induced mitochondrial ROS overproduction and Ang II-mediated Ca²⁺ release in vascular smooth muscle cells (VSMC). The effect of mitochondrial ROS on AT₁ expression, and Ca²⁺ and IP₃ generation was studied in 2 VSMC models of metabolic syndrome using fura-2/AM probes and ELISA-based assay. Ang II-mediated aortic ring contraction in SD rats fed with high-fat diet (HFD) was measured using a force transducer connected to chart recorder. In the metabolic syndrome, almost 2-fold increased mitochondrial O₂ ⁻ significantly upregulated AT₁ expressions by ~60%, companied by elevated Ca²⁺ and IP₃ levels in VSMC and enhanced aortic rings contraction. All these increments were blocked by rotenone (inhibitor of mitochondrial respiratory chain complex I), ruthenium red (inhibitor of calcium uniporter), cyclosporin A (inhibitor of mitochondrial permeability pore), and N-acetylcysteine. Therefore, in the states of metabolic syndrome, ROS overproduction in mitochondrial complex I enhances Ang II-mediated vascular contraction via an AT₁-dependent pathway. In addition, the import of Ca²⁺ from endoplasmic reticulum to mitochondria via calcium uniporter and mitochondrial permeability pore seems to serve as a mechanism to further aggravate mitochondrial damage and vascular dysfunction that may contribute to the occurrence of hypertension.

Key words

mitochondria - reactive oxygen species - mitochondrial calcium uniporter - mitochondrial permeability transition pore

• References

• 1 Reaven G. Metabolic syndrome: pathophysiology and implications for management of cardiovascular disease. Circulation 2002; 106: 286-288
• 2 Cuspidi C, Meani S, Fusi V, Severgnini B, Valerio C, Catini E, Leonetti G, Magrini F, Zanchetti A. Metabolic syndrome and target organ damage in untreated essential hypertensives. J Hypertens 2004; 22: 1991-1998
• 3 Schillaci G, Pirro M, Vaudo G, Gemelli F, Marchesi S, Porcellati C, Mannarino E. Prognostic value of the metabolic syndrome in essential hypertension. J Am Coll Cardiol 2004; 43: 1817-1822
• 4 Pechanova O, Simko F. Chronic antioxidant therapy fails to ameliorate hypertension: potential mechanisms behind. J Hypertens Suppl 2009; 27: S32-S36
• 5 Madamanchi NR, Vendrov A, Runge MS. Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol 2005; 25: 29-38
• 6 Grattagliano I, Palmieri VO, Portincasa P, Moschetta A, Palasciano G. Oxidative stress-induced risk factors associated with the metabolic syndrome: a unifying hypothesis. J Nutr Biochem 2008; 19: 491-504
• 7 Touyz RM, Schiffrin EL. Reactive oxygen species in vascular biology: implications in hypertension. Histochem Cell Biol 2004; 122: 339-352
• 8 Blanc A, Pandey NR, Srivastava AK. Synchronous activation of ERK 1/2, p38mapk and PKB/Akt signaling by H₂O₂ in vascular smooth muscle cells: potential involvement in vascular disease (review). Int J Mol Med 2003; 11: 229-234
• 9 Ushio-Fukai M, Alexander RW, Akers M, Griendling KK. p38 Mitogen-activated protein kinase is a critical component of the redox-sensitive signaling pathways activated by angiotensin II. Role in vascular smooth muscle cell hypertrophy. J Biol Chem 1998; 273: 15022-15029
• 10 Viedt C, Soto U, Krieger-Brauer HI, Fei J, Elsing C, Kübler W, Kreuzer J. Differential activation of mitogen-activated protein kinases in smooth muscle cells by angiotensin II: involvement of p22phox and reactive oxygen species. Arterioscler Thromb Vasc Biol 2000; 20: 940-948
• 11 Wassmann S, Laufs U, Bäumer AT, Müller K, Konkol C, Sauer H, Böhm M, Nickenig G. Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. Mol Pharmacol 2001; 59: 646-654
• 12 Touyz RM, Yao G, Schiffrin EL. c-Src induces phosphorylation and translocation of p47phox: role in superoxide generation by angiotensin II in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2003; 23: 981-987
• 13 Zalba G, San José G, Moreno MU, Fortuño MA, Fortuño A, Beaumont FJ, Díez J. Oxidative stress in arterial hypertension: role of NAD(P)H oxidase. Hypertension 2001; 38: 1395-1399
• 14 Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol 2004; 287: C817-C833
• 15 Bernardi P, Broekemeier KM, Pfeiffer DR. Recent progress on regulation of the mitochondrial permeability transition pore; a cyclosporin-sensitive pore in the inner mitochondrial membrane. J Bioenerg Biomembr 1994; 26: 509-517
• 16 Zhang ZF, Li Q, Liang J, Dai XQ, Ding Y, Wang JB, Li Y. Epigallocatechin-3-O-gallate (EGCG) protects the insulin sensitivity in rat L6 muscle cells exposed to dexamethasone condition. Phytomedicine 2010; 17: 14-18
• 17 Meigs JB, Wilson PW, Fox CS, Vasan RS, Nathan DM, Sullivan LM, D’Agostino RB. Body mass index, metabolic syndrome, and risk of type 2 diabetes or cardiovascular disease. J Clin Endocrinol Metab 2006; 91: 2906-2912
• 18 Cangemi R, Angelico F, Loffredo L, Del Ben M, Pignatelli P, Martini A, Violi F. Oxidative stress-mediated arterial dysfunction in patients with metabolic syndrome: Effect of ascorbic acid. Free Radic Biol Med 2007; 43: 853-859
• 19 Delbosc S, Paizanis E, Magous R, Araiz C, Dimo T, Cristol JP, Cros G, Azay J. Involvement of oxidative stress and NADPH oxidase activation in the development of cardiovascular complications in a model of insulin resistance, the fructose-fed rat. Atherosclerosis 2005; 179: 43-49
• 20 Zhou MS, Schulman IH, Raij L. Role of angiotensin II and oxidative stress in vascular insulin resistance linked to hypertension. Am J Physiol Heart Circ Physiol 2009; 296: H833-H859
• 21 Ramachandran A, Levonen AL, Brookes PS, Ceaser E, Shiva S, Barone MC, Darley-Usmar V. Mitochondria, nitric oxide, and cardiovascular dysfunction. Free Radic Biol Med 2002; 33: 1465-1474
• 22 Irani K. Oxidant signaling in vascular cell growth, death, and survival: a review of the roles of reactive oxygen species in smooth muscle and endothelial cell mitogenic and apoptotic signaling. Circ Res 2000; 87: 179-183
• 23 Clempus RE, Griendling KK. Reactive oxygen species signaling in vascular smooth muscle cells. Cardiovasc Res 2006; 71: 216-225
• 24 He P, Klein J, Yun CC. Activation of Na+/H+ exchanger NHE3 by angiotensin II is mediated by inositol 1,4,5-triphosphate (IP3) receptor-binding protein released with IP3 (IRBIT) and Ca2+/calmodulin-dependent protein kinase II. J Biol Chem 2010; 285: 27869-27878
• 25 Kuznetsov AV, Guzun R, Boucher F, Bagur R, Kaambre T, Saks V. Mysterious Ca(2+)-independent muscular contraction: déjà vu. Biochem J 2012; 445: 333-336
• 26 Minamino T, Komuro I, Kitakaze M. Endoplasmic reticulum stress as a therapeutic target in cardiovascular disease. Circ Res 2010; 107: 1071-1082
• 27 Szabadkai G, Duchen MR. Mitochondria: the hub of cellular Ca2+ signaling. Physiology 2008; 23: 84-94
• 28 Saotome M, Katoh H, Satoh H, Nagasaka S, Yoshihara S, Terada H, Hayashi H. Mitochondrial membrane potential modulates regulation of mitochondrial Ca2+ in rat ventricular myocytes. Am J Physiol Heart Circ Physiol 2005; 288: H1820-H1828
• 29 Kirichok Y, Krapivinsky G, Clapham DE. The mitochondrial calcium uniporter is a highly selective ion channel. Nature 2004; 427: 360-364
• 30 Michels G, Khan IF, Endres-Becker J, Rottlaender D, Herzig S, Ruhparwar A, Wahlers T, Hoppe UC. Regulation of the human cardiac mitochondrial Ca2+ uptake by 2 different voltage-gated Ca2+ channels. Circulation 2009; 119: 2435-2443
• 31 Duchen MR. Roles of mitochondria in health and disease. Diabetes 2004; 53: S96-S102
• 32 Csordás G, Hajnóczky G. SR/ER-mitochondrial local communication: calcium and ROS. Biochim Biophys Acta 2009; 1787: 1352-1362
• 33 Rizzuto R, Marchi S, Bonora M, Aguiari P, Bononi A, De Stefani D, Giorgi C, Leo S, Rimessi A, Siviero R, Zecchini E, Pinton P. Ca(2+) transfer from the ER to mitochondria: when, how and why. Biochim Biophys Acta 2009; 1787: 1342-1351
• 34 McCormack JG, Halestrap AP, Denton RM. Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev 1990; 70: 391-425