Role of protein disulfide isomerase in vascular reactivity to angiotensin II in spontaneously hypertensive rats: possible involvement of NADPH oxidase

• Grant number: 09/15257-1
• Support Opportunities: Regular Research Grants
• Duration: April 01, 2010 - March 31, 2012
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Lucia Rossetti Lopes
• Grantee: Lucia Rossetti Lopes
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Hypertension affects 30% of adults in the western world and is the leading cause of worldwide death and morbidity. Mechanisms leading to high blood pressure remain largely unknown. Among the many factors implicated in the pathophysiology of hypertension, compelling evidence indicate that reactive oxygen species (ROS) are important players. Hypertension has been associated to structural alterations in the vasculature due to an excessive generation of ROS which disrupts redox signaling and activates pathological pathways in a process known as oxidative stress. Factors contributing to oxidative stress in hypertension include decreased antioxidant activity , reduced level of ROS scavengers and activation of phagocytic and non phagocytic NADPH oxidase. In experimental models convincing data indicate that oxidative stress plays a role in the pathophysiology of hypertension particularly in Ang II dependent forms of hypertension. Mice deficient in ROS-generating enzymes have lower blood pressure compared with wild type counterparts and Ang II infusion fails to induce hypertension in these mice. In fact, in cultured vascular smooth muscle cells (VSMCs) and isolated arteries from hypertensive rats and humans, NADPH oxidase is up regulated and ROS production is enhanced. Molecular processes underlying ROS-induced cardiovascular functional and structural alterations involve activation of redox sensitive signaling pathways. Superoxide anion and H2O2 stimulate mitogen activated protein kinases, tyrosine kinases and transcription factors and inactivate protein tyrosine phosphatases. ROS also increase intracellular calcium concentration and activate RhoA/Rho kinase leading to increased actin/myosin coupling and contraction. These effects occur through oxidative modification of proteins by altering key aminoacid residues such as cysteines in proteins. Although numerous studies have indicated that anti oxidants and ROS scavenging could prevent hypertension, extending this concept into the treatment of cardiovascular diseases has been problematic. In fact, several clinical trials have failed to show any benefits of antioxidant vitamins in prevention of cardiovascular disease. A highly likely reason is that ROS have important signaling properties and the non selective approach of scavenging all ROS could have deleterious effects. Another alternative to reduce oxidative stress is to interfere with the activity of the enzymes involved in ROS generation, particularly NADPH oxidase. Ang II is the most important stimuli of vascular NADPH oxidase activity and expression. We recently demonstrated that the redox endoplasmatic reticulum chaperone protein disulfide isomerase (PDI) modulates Ang II dependent dependent ROS generation in VSMCs. PDI associates with several isoforms of NADPH oxidase including Nox1,Nox2 and Nox4. Importantly an increase in Nox 1 expression has been associated to an increase in ROS generation in Ang II -induced hypertension. Furthermore, over expression of PDI increases ROS generation and NADPH oxidase expression in rabbit aortic smooth muscle cells. However, the role of PDI in oxidative stress and vascular alterations observed in hypertension is unknown. The goal of the present study is to evaluate the effect of PDI in the vascular reactivity to Ang II and NADPH oxidase activation in resistant arteries of spontaneous hypertensive rats. Our results could implicate PDI as a novel player in Ang II redox signaling and particularly in the oxidative stress and vascular dysfunction associated to hypertension. (AU)