Adiponectin attenuates cyclophilin A induced vascular remodeling in response to mechanical stretch and angiotensin-II -

Abstract

Obesity is among the world major public health problems. It is associated with cardiovascular diseases (CVD) including hypertension and other comorbid conditions. However, the mechanisms that contribute to the development of hypertension leading to CVD have not been fully-elucidated. Increased vascular pressure is associated with stimulation of membrane bound NADPH oxidase; as a result, the formation of reactive oxygen species (ROS) in vascular smooth muscle cells (VSMC) increases dramatically. Of note, ROS play a key pathophysiological role in developing CVD. In addition, ROS has been associated with the secretion of Cyclophlin A (CyPA, oxidative stress marker). CyPA was first identified as the primary intracellular binding target of the immunosuppressant cyclosporin A; however, studies have shown its incorporation in CVD. Moreover, Obesity is associated with decrease in adiponectin (adipocytokine of 30 kDa) levels. Several studies have revealed that adiponectin preserves the normal physiology of the heart by protecting the heart and blood vessels against atherosclerosis, inflammatory, and oxidative stress. In this study, we aimed to investigate whether hypertension-mechanical stretch enhances the overexpression of CyPA protein and to explore the molecular mechanisms that mediates stretch-induced CyPA expression. We will also assess the different possible pathways of CyPA induced vascular remodeling. We will focus on the protective effects of adiponectin and its effects on CyPA protein expression. Methods: Rat portal veins (RPV) organ culture with or without stretching along with aorta organ culture with or without angiotensin-II (Ang-II) were performed to study CyPA protein expression. Some experiments needed treatment with an inhibitor (apocynin, Y- 27632, cyclosporine-A) or adiponectin one hour prior to stretch or Ang-II treatment. CyPA treatment for different times was also done on aorta and RPV. Western blot was used to study the expression of various proteins (CyPA, ERK1-2, p 38, p-eNOS, p-AMPK). Immunoh