Advancing the health and well-being of animals and people

Principal Investigator:  Heinrich Lob

Department of Biomedical Sciences
Contact Information: Email:; Phone: 607-253-3677
Sponsor: American Heart Association- National Center
Grant Number: 12SDG9160010
Title: Central Mechanisms of Angiotensin-dependent Hypertension: NADPH Oxidase Insoforms and Endoplasmic Reticulum Stress
Annual Direct Cost: $70,000
Project Period: 01/01/2012-12/31/2015

DESCRIPTION (provided by applicant): Reactive oxygen species (ROS) are metabolites of oxygen that contribute to the pathogenesis of numerous cardiovascular diseases including hypertension. Recent studies show that superoxide in the circumventricular subfornical organ (SFO), a brain region that lacks a blood-brain-barrier and is critical in cardiovascular regulation, causes vascular T cell infiltration and hypertension. The NADPH oxidase (Nox) is a key source of oxidative stress in the SFO. However, the molecular mechanisms by which Ang-II is linked to specific Nox homologue activation in the SFO, and how this translates to sympathetic activation, peripheral inflammation and hypertension is not known. The endoplasmatic reticulum (ER) is specialized in the synthesis and modification of proteins, and plays an important role in cell signaling processes involving Ca2+ and ROS. Changes in Ca2+ homeostasis, redox homeostasis or increased protein load - all effects of Ang-II stimulation - lead to "ER stress". This triggers an adaptive program known as the unfolded protein response (UPR), which is a series of signaling cascades designed to re-establish ER homeostasis. It is thought that long-term activation of the UPR leads to chronic diseases such as diabetes, obesity, heart failure and atherosclerosis, all known to involve oxidative stress. However, the role of ER stress in hypertension is not known. Our recent data show that "slow-pressor" Ang-II hypertension, a chronic mouse model that recapitulates key features of essential human essential hypertension, causes ER stress in the SFO. I will address the central hypothesis that slow pressor Ang-II HTN involves Nox2 and/or Nox4-dependent ER stress in the SFO, and this leads to sympathoexcitation, peripheral inflammation and HTN.