PPARγ receptor plays an important role in oxidative stress response. Its agonists can influence vascular contractility in experimental hypertension. Our study was focused on the effects of a PPARγ agonist pioglitazone (PIO) on blood pressure regulation, vasoactivity of vessels, and redox-sensitive signaling at the central (brainstem, BS) and peripheral (left ventricle, LV) levels in young prehypertensive rats. 5-week-old SHR were treated either with PIO (10？mg/kg/day, 2 weeks) or with saline using gastric gavage. Administration of PIO significantly slowed down blood pressure increase and improved lipid profile and aortic relaxation after insulin stimulation. A significant increase in PPARγ expression was found only in BS, not in LV. PIO treatment did not influence NOS changes, but had tissue-dependent effect on SOD regulation and increased SOD activity, observed in LV. The treatment with PIO differentially affected also the levels of other intracellular signaling components: Akt kinase increased in the the BS, while β-catenin level was down-regulated in the BS and up-regulated in the LV. We found that the lowering of blood pressure in young SHR can be connected with insulin sensitivity of vessels and that β-catenin and SOD levels are important agents mediating PIO effects in the BS and LV. 1. Introduction Blood pressure is regulated by several internal systems. Power-spectral analysis identifies oscillations in heart rate and blood pressure that are modulated by inputs from the renin-angiotensin system, sympathetic and parasympathetic neurons, and locally released vasoactive factors such as nitric oxide (NO). Current findings support the view that the reactive oxygen species (ROS) and antioxidant enzymes such as superoxide dismutase (SOD) expressed in the central nervous system (CNS) play an important role in the regulation of blood pressure, and perturbations in redox homeostasis contribute to pathogenesis of hypertension [1]. Activity of ROS sources (such as NADPH oxidases), stimulated through angiotensin II system and AT1 receptors are involved in redox-sensitive intracellular signaling modulated by kinase cascades and transcriptional factors in cardiovascular system [2]. Antioxidant response and the potential sites of internal antioxidants of different SOD isoforms, could modulate blood pressure in the vasculature, the brain, and the kidney [1, 2]. The peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that takes part in the regulation of lipid metabolism and in cellular signaling. Dysregulation in the PPARγ activity may
References
[1]
H. E. Lob, P. J. Marvar, T. J. Guzik et al., “Induction of hypertension and peripheral inflammation by reduction of extracellular superoxide dismutase in the central nervous system,” Hypertension, vol. 55, no. 2, pp. 277–283, 2010.
[2]
M. Majzunova, I. Dovinova, M. Barancik, and J. Y. Chan, “Redox signaling in pathophysiology of hypertension,” Journal of Biomedical Science, vol. 20, no. 1, p. 69, 2013.
[3]
S. Polvani, M. Tarocchi, and A. Galli, “PPAR and oxidative stress: Con(β) catenating NRF2 and FOXO,” PPAR Research, vol. 2012, Article ID 641087, 15 pages, 2012.
[4]
K. L. Houseknecht, B. M. Cole, and P. J. Steele, “Peroxisome proliferator-activated receptor gamma (PPARγ) and its ligands: a review,” Domestic Animal Endocrinology, vol. 22, no. 1, pp. 1–23, 2002.
[5]
J. M. Kleinhenz, D. J. Kleinhenz, S. You et al., “Disruption of endothelial peroxisome proliferator-activated receptor-γ reduces vascular nitric oxide production,” American Journal of Physiology, vol. 297, no. 5, pp. H1647–H1654, 2009.
[6]
S. H. H. Chan, K. L. H. Wu, P. S. S. Kung, and J. Y. H. Chan, “Oral intake of rosiglitazone promotes a central antihypertensive effect via upregulation of peroxisome proliferator-activated receptor-γ and alleviation of oxidative stress in rostral ventrolateral medulla of spontaneously hypertensive rats,” Hypertension, vol. 55, no. 6, pp. 1444–1453, 2010.
[7]
R. Li, H. Zhang, W. Wang et al., “Vascular insulin resistance in prehypertensive rats: role of PI3-kinase/Akt/eNOS signaling,” European Journal of Pharmacology, vol. 628, no. 1–3, pp. 140–147, 2010.
[8]
D. Gao, N. Ning, G. Hao, and X. Niu, “Pioglitazone attenuates vascular fibrosis in spontaneously hypertensive rats,” PPAR Research, vol. 2012, Article ID 856426, 7 pages, 2012.
[9]
G. Ding, M. Fu, Q. Qin et al., “Cardiac peroxisome proliferator-activated receptor γ is essential in protecting cardiomyocytes from oxidative damage,” Cardiovascular Research, vol. 76, no. 2, pp. 269–279, 2007.
[10]
Y. Okuno, M. Matsuda, Y. Miyata et al., “Human catalase gene is regulated by peroxisome proliferator activated receptor-gamma through a response element distinct from that of mouse,” Endocrine Journal, vol. 57, no. 4, pp. 303–309, 2010.
[11]
G. D. Girnun, F. E. Domann, S. A. Moore, and M. E. C. Robbins, “Identification of a functional peroxisome proliferator-activated receptor response element in the rat catalase promoter,” Molecular Endocrinology, vol. 16, no. 12, pp. 2793–2801, 2002.
[12]
Y. Zhao, A. Patzer, T. Herdegen, P. Gohlke, and J. Culman, “Activation of cerebral peroxisome proliferator-activated receptors gamma promotes neuroprotection by attenuation of neuronal cyclooxygenase-2 overexpression after focal cerebral ischemia in rats,” The FASEB Journal, vol. 20, no. 8, pp. 1162–1175, 2006.
[13]
M. Collino, M. Aragno, R. Mastrocola et al., “Modulation of the oxidative stress and inflammatory response by PPAR-γ agonists in the hippocampus of rats exposed to cerebral ischemia/reperfusion,” European Journal of Pharmacology, vol. 530, no. 1-2, pp. 70–80, 2006.
[14]
Y. Birnbaum, B. Long, J. Qian, J. R. Perez-Polo, and Y. Ye, “Pioglitazone limits myocardial infarct size, activates Akt, and upregulates cPLA2 and COX-2 in a PPAR-γ-independent manner,” Basic Research in Cardiology, vol. 106, no. 3, pp. 431–446, 2011.
[15]
S. Yasuda, H. Kobayashi, M. Iwasa et al., “Antidiabetic drug pioglitazone protects the heart via activation of PPAR-γ receptors, PI3-kinase, Akt, and eNOS pathway in a rabbit model of myocardial infarction,” American Journal of Physiology, vol. 296, no. 5, pp. H1558–H1565, 2009.
[16]
S. Goetze, F. Eilers, A. Bungenstock et al., “PPAR activators inhibit endothelial cell migration by targeting Akt,” Biochemical and Biophysical Research Communications, vol. 293, no. 5, pp. 1431–1437, 2002.
[17]
Y. Xiao, T. Yuan, W. Yao, and K. Liao, “3T3-L1 adipocyte apoptosis induced by thiazolidinediones is peroxisome proliferator-activated receptor-γ-dependent and mediated by the caspase-3-dependent apoptotic pathway,” FEBS Journal, vol. 277, no. 3, pp. 687–696, 2010.
[18]
D. Fang, D. Hawke, Y. Zheng et al., “Phosphorylation of β-catenin by AKT promotes β-catenin transcriptional activity,” Journal of Biological Chemistry, vol. 282, no. 15, pp. 11221–11229, 2007.
[19]
D. Hoogeboom and B. M. T. Burgering, “Should I stay or should I go: β-catenin decides under stress,” Biochimica et Biophysica Acta, vol. 1796, no. 2, pp. 63–74, 2009.
[20]
J. Kopincová, A. Púzserová, and I. Bernátová, “Chronic low-dose L-NAME treatment effect on cardiovascular system of borderline hypertensive rats: feedback regulation?” Neuroendocrinology Letters, vol. 29, no. 5, pp. 784–789, 2008.
[21]
M. Shargorodsky, K. Michaelova, M. Boaz, D. Gavish, and R. Zimlichman, “Effect of long-term treatment with rosiglitazone on arterial elasticity and metabolic parameters in patients with type 2 diabetes mellitus: a 2-year follow-up study,” Diabetic Medicine, vol. 24, no. 11, pp. 1254–1260, 2007.
[22]
M. Pravenec, V. Zídek, V. Landa et al., “Age-related autocrine diabetogenic effects of transgenic resistin in spontaneously hypertensive rats: gene expression profile analysis,” Physiological Genomics, vol. 43, no. 7, pp. 372–379, 2011.
[23]
M. Collino, M. Aragno, S. Castiglia et al., “Pioglitazone improves lipid and insulin levels in overweight rats on a high cholesterol and fructose diet by decreasing hepatic inflammation,” British Journal of Pharmacology, vol. 160, no. 8, pp. 1892–1902, 2010.
[24]
M. Barbieri, C. Di Filippo, A. Esposito et al., “Effects of PPARs agonists on cardiac metabolism in littermate and cardiomyocyte-specific PPAR-γ -knockout (CM-PGKO) mice,” PLoS ONE, vol. 7, no. 4, Article ID e35999, 2012.
[25]
Y. Ye, Y. Lin, S. Atar et al., “Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions,” American Journal of Physiology, vol. 291, no. 3, pp. H1158–H1169, 2006.
[26]
D. H. Kim, S. C. Woods, and R. J. Seeley, “Hypothalamic Akt/PKB signaling in regulation of food intake,” Fronteer in Bioscience, vol. 4, pp. 953–966, 2012.
[27]
H. Kawabata and K. Ishikawa, “Cardioprotection with pioglitazone is abolished by nitric oxide synthase inhibitor in ischemic rabbit hearts—comparison of the effects of pioglitazone and metformin,” Diabetes/Metabolism Research and Reviews, vol. 19, no. 4, pp. 299–305, 2003.
[28]
K. Nishio, M. Shigemitsu, Y. Kodama et al., “The effect of pioglitazone on nitric oxide synthase in patients with type 2 diabetes mellitus,” Journal of the cardiometabolic syndrome, vol. 3, no. 4, pp. 200–204, 2008.
[29]
A. Kondrashov, S. Vranková, I. Dovinová et al., “The effects of new Alibernet red wine extract on nitric oxide and reactive oxygen species production in spontaneously hypertensive rats,” Oxidative Medicine and Cellular Longevity, vol. 2012, Article ID 806285, 8 pages, 2012.
[30]
A. H. Dorafshar, K. Moodley, M. Khoe, C. Lyon, and M. Bryer-Ash, “Pioglitazone improves superoxide dismutase mediated vascular reactivity in the obese Zucker rat,” Diabetes and Vascular Disease Research, vol. 7, no. 1, pp. 20–27, 2010.
[31]
A. Gumieniczek, ？. Komsta, and M. R. Chehab, “Effects of two oral antidiabetics, pioglitazone and repaglinide, on aconitase inactivation, inflammation and oxidative/nitrosative stress in tissues under alloxan-induced hyperglycemia,” European Journal of Pharmacology, vol. 659, no. 1, pp. 89–93, 2011.
[32]
G. D. Girnun, W. M. Smith, S. Drori et al., “APC-dependent suppression of colon carcinogenesis by PPARγ,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 21, pp. 13771–13776, 2002.
[33]
T.-P. Alastalo, M. Li, V. De Jesus Perez et al., “Disruption of PPARγ/β-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival,” The Journal of Clinical Investigation, vol. 121, no. 9, pp. 3735–3746, 2011.
[34]
D. Lu and D. A. Carson, “Repression of β-catenin signaling by PPARγ ligands,” European Journal of Pharmacology, vol. 636, no. 1–3, pp. 198–202, 2010.
[35]
C. Sharma, A. Pradeep, L. Wong, A. Rana, and B. Rana, “Peroxisome proliferator-activated receptor γ activation can regulate β-catenin levels via a proteasome-mediated and adenomatous polyposis coli-independent pathway,” Journal of Biological Chemistry, vol. 279, no. 34, pp. 35583–35594, 2004.
[36]
Y. Kanda, M. Matsuda, K. Tawaramoto et al., “Effects of sulfonylurea drugs on adiponectin production from 3T3-L1 adipocytes: implication of different mechanism from pioglitazone,” Diabetes Research and Clinical Practice, vol. 81, no. 1, pp. 13–18, 2008.
[37]
J. MacKellar, S. W. Cushman, and V. Periwal, “Differential effects of thiazolidinediones on adipocyte growth and recruitment in Zucker fatty rats,” PLoS ONE, vol. 4, no. 12, Article ID e8196, 2009.
[38]
J. G. Kang, C.-Y. Park, S.-H. Ihm et al., “Mechanisms of adipose tissue redistribution with rosiglitazone treatment in various adipose depots,” Metabolism, vol. 59, no. 1, pp. 46–53, 2010.
[39]
A. Harte, P. McTernan, R. Chetty et al., “Insulin-mediated upregulation of the renin angiotensin system in human subcutaneous adipocytes is reduced by rosiglitazone,” Circulation, vol. 111, no. 15, pp. 1954–1961, 2005.
[40]
A. Saiki, M. Ohira, K. Endo et al., “Pioglitazone decreases plasma angiotensin II concentration in type 2 diabetes,” Journal of Atherosclerosis and Thrombosis, vol. 17, no. 6, pp. 651–657, 2010.
