Infliximab prevents increased systolic blood pressure and upregulates the AKT/eNOS pathway in the aorta of spontaneously hypertensive rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)High systolic blood pressure caused by endothelial dysfunction is a comorbidity of metabolic syndrome that is mediated by local inflammatory signals. Insulin-induced vasorelaxation due to endothelial nitric oxide synthase (eNOS) activation is highly dependent on the activation of the upstream insulin-stimulated serine/threoninekinase (AKT) and is severely impaired in obese, hypertensive rodents and humans. Neutralisation of circulating tumor necrosis factor-alpha (TNF alpha) with infliximab improves glucose homeostasis, but the consequences of this pharmacological strategy on systolic blood pressure and eNOS activation are unknown. To address this issue, we assessed the temporal changes in the systolic pressure of spontaneously hypertensive rats (SHR) treated with infliximab. We also assessed the activation of critical proteins that mediate insulin activity and TNF alpha-mediated insulin resistance in the aorta and cardiac left ventricle. Our data demonstrate that infliximab prevents the upregulation of both systolic pressure and left ventricle hypertrophy in SHR. These effects paralleled an increase in AKT/eNOS phosphorylation and a reduction in the phosphorylation of inhibitor of nuclear factor-kappa B (I kappa beta) and c-Jun N-terminal kinase (JNK) in the aorta. Overall, our study revealed the cardiovascular benefits of infliximab in SHR. In addition, the present findings further suggested that the reduction of systolic pressure and left ventricle hypertrophy by infliximab are secondary effects to the reduction of endothelial inflammation and the recovery of AKT/eNOS pathway activation. (C) 2012 Elsevier B.V. All rights reserved.70041699201209Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

L-name-induced Hypertension Does Not Completely Reproduce The Hemodynamic Pattern Of The Hypertensive-diabetic Cardiomyopathy In Rats

Renovascular hypertension (2K1C) + type 1 diabetes mimics the morphological abnormalities described in the cardiomyopathy induced by L-NAME in rats, but their hemodynamic patterns are still controversial. The present study investigated the cardiovascular function in these two models of cardiomyopathy in rats after 8 weeks of treatment. Wistar rats were divided into the following groups: Control (C); L-NAME (L)-60 mg/kg/ day; 2K1C+DM (R+D)-streptozotocin (60 mg/kg) and one renal artery clipped. The following parameters were measured: mean arterial pressure (MAP), heart rate, cardiac output (CO) and total peripheral vascular resistance (TPVR). dP/dt+ and dP/dt- were also evaluated in an isolated heart setup. L and R+D groups had increased MAP (175.4±29.7 and 158.7±16.7 mmHg, respectively) and reduced CO after the 8th week. TPVR was increased in both groups. A decrease in dP/dt+ was found in the R+D (1895±98 mmHg/s, p<0.05) vs. C group (2534±120 mmHg/ s, p< 0.05). dP/dt- was diminished in the L and R+D groups vs. C group (1490±104 and 1460±94 mmHg/s, respectively vs. 2080±92 mmHg/s, p<0.05). Our study indicates that the hemodynamic abnormalities found in R+D and L-induced cardiomyopathies are not quite similar as well as their previously described histopathological features.314449Moncada, S., Palmer, R.M., Higgs, E.A., Nitric oxide: Physiology, pathophysiology, and pharmacology (1991) Pharmacol Rev, 43 (2), pp. 109-142. , Jun;Arnal, J.F., el Amrani, A.I., Chatellier, G., Menard, J., Michel, J.B., Cardiac weight in hypertension induced by nitric oxide synthase blockade (1993) Hypertension, 22 (3), pp. 380-387. , Sep;Moreno Júnior, H., Metze, K., Zatz, R., De Nucci, G., Chronic nitric oxide blockade causes cardiac ischaemia but not cardiac hypertrophy: An experiment of four weeks in rats (1994) Verh Dtsch Ges Path, 78, p. 459Pechánová, O., Bernátová, I., Effect of long-term NO synthase inhibition on cyclic nucleotide content in rat tissues (1996) Physiol Res, 45 (4), pp. 305-309Babál, P., Pechánová, O., Bernátová, I., Stvrtina, S., Chronic inhibition of NO synthesis produces myocardial fibrosis and arterial media hyperplasia (1997) Histol Histopathol, 12 (3), pp. 623-629. , Jul;Bernátová, I., Pechánová, O., Kristek, F., Mechanism of structural remodelling of the rat aorta during long-term NG-nitro-L-arginine methyl ester treatment (1999) Jpn J Pharmacol, 81 (1), pp. 99-106. , Sep;Pechánová, O., Bernátová, I., Babál, P., Structural alterations in the heart after long-term L-NAME and D-NAME treatment (1999) Gen Physiol Biophys, 18 (SUPPL. 1), pp. 6-9. , Dec;Lip, G.Y., Felmeden, D.C., Li-Saw-Hee, F.L., Beevers, D.G., Hypertensive heart disease. A complex syndrome or a hypertensive 'cardiomyopathy'? (2000) Eur Heart J, 21 (20), pp. 1653-1665. , Oct;Grossman, E., Messerli, F.H., Diabetic and hypertensive heart disease (1996) Ann Intern Med, 125 (4), pp. 304-310. , Aug 15;Sowers, J.R., Epstein, M., Frohlich, E.D., Diabetes, hypertension, and cardiovascular disease: An update (2001) Hypertension, 37 (4), pp. 1053-1059. , Apr;Factor, S.M., Minase, T., Cho, S., Capasso, J.M., Sonnenblick, E.H., Coronary microvascular abnormalities in the hypertensive-diabetic rat. A primary cause of cardiomyopathy? (1984) Am J Pathol, 116 (1), pp. 9-20. , Jul;Mathis, D.R., Liu, S.S., Rodrigues, B.B., McNeill, J.H., Effect of hypertension on the development of diabetic cardiomyopathy (2000) Can J Physiol Pharmacol, 78 (10), pp. 791-798. , Oct;Kojda, G., Harrison, D., Interactions between NO and reactive oxygen species: Pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure (1999) Cardiovasc Res, 43 (3), pp. 562-571. , Aug 15;Bayraktutan, U., Yang, Z.K., Shah, A.M., Selective dysregulation of nitric oxide synthase type 3 in cardiac myocytes but not coronary microvascular endothelial cells of spontaneously hypertensive rat (1998) Cardiovasc Res, 38 (3), pp. 719-726. , Jun;Hink, U., Li, H., Mollnau, H., Oelze, M., Matheis, E., Hartmann, M., Skatchkov, M., Munzel, T., Mechanisms underlying endothelial dysfunction in diabetes mellitus (2001) Circ Res, 88 (2), pp. E14-E22. , Feb 2;Sampaio, R.C., Tanus-Santos, J.E., Melo, S.E., Hyslop, S., Franchini, K.G., Luca, I.M., Moreno Jr, H., Hypertension plus diabetes mimics the cardiomyopathy induced by nitric oxide inhibition in rats (2002) Chest, 122 (4), pp. 1412-1420. , Oct;Goldblatt, H., Lynch, J., Hanzal, R.F., Summerville, W.W., Studies on experimental hypertension. The production of persistent elevation of systolic blood pressure by means of renal ischemia (1934) J Exp Med, 59, pp. 347-379Moreno Jr, H., Metze, K., Antunes, E., Zatz, R., De Nucci, G., Chronic nitric oxide inhibition as a model of hypertensive heart muscle disease (1996) Basic Res Cardiol, 91 (3), pp. 248-255. , May-Jun;Zatz, R., A low cost tail-cuff method for the estimation of mean arterial pressure in conscious rats (1990) Lab Anim Sci, 40 (2), pp. 198-201. , Mar;Langendorff, Untersuchungen am überlebenden Säugethierherzen. (1895) Pflügers Arch Ges Physiol, pp. 291-332Sigmon, D., Beierwaltes, W.H., Influence of nitric oxide in the chronic phase of two-kidney, one clip renovascular hypertension (1998) Hypertension, 31 (2), pp. 649-656. , Feb;Zhong, N., Zhang, Y., Zhu, H.F., Wang, J.C., Fang, Q.Z., Zhou, Z.N., Myocardial capillary angiogenesis and coronary flow in ischemia tolerance rat by adaptation to intermittent high altitude hypoxia (2002) Acta Pharmacol Sin, 23 (4), pp. 305-310. , Apr;Fredersdorf, S., Thumann, C., Ulucan, C., Griese, D.P., Luchner, A., Riegger, G.A., Kromer, E.P., Weil, J., Myocardial hypertrophy and enhanced left ventricular contractility in Zucker diabetic fatty rats (2004) Cardiovasc Pathol, 13 (1), pp. 11-19. , Jan-Feb;Sun, Y., Zhang, J., Lu, L., Bedigian, M.P., Robinson, A.D., Weber, K.T., Tissue angiotensin II in the regulation of inflammatory and fibrogenic components of repair in the rat heart (2004) J Lab Clin Med, 143 (1), pp. 41-51. , Jan;Matsubara, B.B., Matsubara, L.S., Zornoff, L.A., Franco, M., Janicki, J.S., Left ventricular adaptation to chronic pressure overload induced by inhibition of nitric oxide synthase in rats (1998) Basic Res Cardiol, 93 (3), pp. 173-181. , Jun;Pessanha, M.G., Mandarim-de-Lacerda, C.A., Influence of the chronic nitric oxide synthesis inhibition on cardiomyocytes number (2000) Virchows Arch, 437 (6), pp. 667-674. , Dec;Maejima, Y., Adachi, S., Ito, H., Nobori, K., Tamamori-Adachi, M., Isobe, M., Nitric oxide inhibits ischemia/reperfusion-induced myocardial apoptosis by modulating cyclin A-associated kinase activity (2003) Cardiovasc Res, 59 (2), pp. 308-320. , Aug 1;Pechánová, O., Bernátová, I., Pelouch, V., Babál, P., L-NAME-induced protein remodeling and fibrosis in the rat heart (1999) Physiol Res, 48 (5), pp. 353-362Stockklauser-Färber, K., Ballhausen, T., Laufer, A., Rösen, P., Influence of diabetes on cardiac nitric oxide synthase expression and activity (2000) Biochim Biophys Acta, 1535 (1), pp. 10-20. , Dec 15;Bojunga, J., Dresar-Mayert, B., Usadel, K.H., Kusterer, K., Zeuzem, S., Antioxidative treatment reverses imbalances of nitric oxide synthase isoform expression and attenuates tissue-cGMP activation in diabetic rats (2004) Biochem Biophys Res Commun, 316 (3), pp. 771-780. , Apr 9;Moshage, H., Nitric oxide determinations: Much ado about NO.-thing? (1997) Clin Chem, 43 (4), pp. 553-556. , Apr;Jungersten, L., Edlund, A., Petersson, A.S., Wennmalm, A., Plasma nitrate as an index of nitric oxide formation in man: Analyses of kinetics and confounding factors (1996) Clin Physiol, 16 (4), pp. 369-379. , Jul;Kobayashi, T., Kamata, K., Effect of chronic insulin treatment on NO production and endothelium-dependent relaxation in aortae from established STZ-induced diabetic rats (2001) Atherosclerosis, 155 (2), pp. 313-320. , Apr;Andrew, P.J., Mayer, B., Enzymatic function of nitric oxide synthases (1999) Cardiovasc Res, 43 (3), pp. 521-531. , Aug 15;Cai, H., Harrison, D.G., Endothelial dysfunction in cardiovascular diseases: The role of oxidant stress (2000) Circ Res, 87 (10), pp. 840-844. , Nov 10;Koo, J.R., Vaziri, N.D., Effects of diabetes, insulin and antioxidants on NO synthase abundance and NO interaction with reactive oxygen species (2003) Kidney Int, 63 (1), pp. 195-201. , Jan

Infliximab prevents increased systolic blood pressure and upregulates the AKT/eNOS pathway in the aorta of spontaneously hypertensive rats

High systolic blood pressure caused by endothelial dysfunction is a comorbidity of metabolic syndrome that is mediated by local inflammatory signals. Insulin-induced vasorelaxation due to endothelial nitric oxide synthase (eNOS) activation is highly dependent on the activation of the upstream insulin-stimulated serine/threonine kinase (AKT) and is severely impaired in obese, hypertensive rodents and humans. Neutralisation of circulating tumor necrosis factor-α (TNFα) with infliximab improves glucose homeostasis, but the consequences of this pharmacological strategy on systolic blood pressure and eNOS activation are unknown. To address this issue, we assessed the temporal changes in the systolic pressure of spontaneously hypertensive rats (SHR) treated with infliximab. We also assessed the activation of critical proteins that mediate insulin activity and TNFα-mediated insulin resistance in the aorta and cardiac left ventricle. Our data demonstrate that infliximab prevents the upregulation of both systolic pressure and left ventricle hypertrophy in SHR. These effects paralleled an increase in AKT/eNOS phosphorylation and a reduction in the phosphorylation of inhibitor of nuclear factor-κB (Iκβ) and c-Jun N-terminal kinase (JNK) in the aorta. Overall, our study revealed the cardiovascular benefits of infliximab in SHR. In addition, the present findings further suggested that the reduction of systolic pressure and left ventricle hypertrophy by infliximab are secondary effects to the reduction of endothelial inflammation and the recovery of AKT/eNOS pathway activation.Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq