Contribution of oxidative stress and NOXes to diabetes-associated vascular injury

• Grant number: 11/01785-6
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): October 01, 2011
• Effective date (End): March 31, 2014
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal researcher: Rita de Cassia Aleixo Tostes Passaglia
• Grantee: Thiago Bruder Do Nascimento
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 11/22035-5 - Contribution of oxidative stress and NADPH oxidase (NOXes) diabetes-associated vascular injury: study in knockout mice, BE.EP.DR

Abstract

Diabetes Mellitus stands out as one of the most important non-transmissible chronic diseases worldwide. It has a major negative impact on the quality of life and exerts a heavy economic burden on the society/ health care system. The prevalence of type 2 diabetes mellitus has increased rapidly in Latin America countries and there is an upward trend among the younger age groups.The prognosis of individuals with diabetes continues to be worse than in age matched non-diabetic individuals and this is related primarily to the long term risk of developing renal and vascular complications. Epidemiological, clinical and experimental data indicate a causal association between hyperglycemia and diabetic complications. Exact mechanisms for this remain elusive but hyperglycaemia-induced oxidative stress appears to play an important role in the increased risk of diabetic complications, including diabetic nephropathy, cardiovascular disease and retinopathy. Myriad sources contribute to increased oxidative stress [increased bioavailability of reactive oxygen species (ROS)], but NADPH oxidase (NOX), may be particularly important in diabetes. This proposal aims to determine the role of NOX1/4-derived ROS in the pathogenesis of diabetic vasculopathy due to type 2 diabetes, to elucidate redox-sensitive molecular mechanisms of the disease and to identify novel therapeutic targets. Our hypothesis is that diabetes is associated with tissue-specific activation of different Nox isoforms: hyperactivation of vascular Nox1 causing vascular injury. This Nox isoform effect is related to differential expression of p47phox and its isoform NOXO1. We will focus on two specific aims: Aim 1. To elucidate the role of Nox1 and Nox4 and p47phox in diabetes-associated vascular complications using a model of diabetic nephropathy, db/db mice (C57BLKS/JLepr), crossed with Nox1-/- and Nox4-/- and p47phox-/- mice. Aim 2. To determine molecular pathways whereby Nox-mediated ROS generation causes diabetes-associated vascular injury. Studies will be performed in isolated vessels and cultured vascular cells (vascular smooth muscle cells, endothelial cells).

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BRUDER-NASCIMENTO, THIAGO; CALLERA, GLAUCIA E.; MONTEZANO, AUGUSTO C.; DE CHANTEMELE, ERIC J. BELIN; TOSTES, RITA C.; TOUYZ, RHIAN M. Atorvastatin inhibits pro-inflammatory actions of aldosterone in vascular smooth muscle cells by reducing oxidative stress. Life Sciences, v. 221, p. 29-34, MAR 15 2019. Web of Science Citations: 0.

BRUDER-NASCIMENTO, THIAGO; CALLERA, GLAUCIA; MONTEZANO, AUGUSTO CESAR; ANTUNES, TAYZE T.; HE, YING; CAT, AURELIE NGUYEN DINH; FERREIRA, NATHANNE S.; BARRETO, PEDRO A.; OLIVON, VANIA C.; TOSTES, RITA C.; TOUYZ, RHIAN M. Renoprotective Effects of Atorvastatin in Diabetic Mice: Downregulation of RhoA and Upregulation of Akt/GSK3. PLoS One, v. 11, n. 9 SEP 20 2016. Web of Science Citations: 4.

BRUDER-NASCIMENTO, THIAGO; CALLERA, GLAUCIA E.; MONTEZANO, AUGUSTO C.; HE, YING; ANTUNES, TAYZE T.; CAT, AURELIE NGUYEN DINH; TOSTES, RITA C.; TOUYZ, RHIAN M. Vascular injury in diabetic db/db mice is ameliorated by atorvastatin: role of Rac1/2-sensitive Nox-dependent pathways. Clinical Science, v. 128, n. 7, p. 411-423, APR 2015. Web of Science Citations: 20.

BRUDER-NASCIMENTO, THIAGO; DA SILVA, MARCONDES A. B.; TOSTES, RITA C. The involvement of aldosterone on vascular insulin resistance: implications in obesity and type 2 diabetes. DIABETOLOGY & METABOLIC SYNDROME, v. 6, AUG 24 2014. Web of Science Citations: 15.

BRUDER-NASCIMENTO, T.; CHINNASAMY, P.; RIASCOS-BERNAL, D. F.; CAU, S. B.; CALLERA, G. E.; TOUYZ, R. M.; TOSTES, R. C.; SIBINGA, N. E. S. Angiotensin II induces Fat1 expression/activation and vascular smooth muscle cell migration via Nox1-dependent reactive oxygen species generation. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, v. 66, p. 18-26, JAN 2014. Web of Science Citations: 33.