The vascular endothelium has an adaptive response to oxidative stress and injurious stimuli that confers powerful and sustained protection against vascular dysfunction. Resistance to endothelial dysfunction and injury is an important protective mechanism as patients with preserved endothelial function are less predisposed to clinical vascular disease such as hypertension and obesity. However, the link between endothelial dysfunction and vascular disease is poorly understood. Previous work has identified the heme oxygenases (HO-1/HO-2), EETs and adiponectin as key endothelial protective molecules. However, the importance of each system and the precise molecular events that determine susceptibility or resistance to endothelial dysfunction are not known. Our published and preliminary data show that: 1) HO-1 induction or overexpression abrogates the injurious consequences of diabetes, obesity and hypertension on the vasculature whereas inhibition of HO activity exacerbates it;2) diminished HO activity increases oxidative stress, inflammation, vascular dysfunction and insulin resistance;3) there is a positive relationship between HO-1 expression and the levels of EET and adiponectin;4) treatment of HO-2-/- mice with an EET agonist rescues the apparent endothelial dysfunction and the inflammatory phenotype;and 5) EET-Tg mice exhibit higher adiponectin levels. Accordingly, we hypothesize that HO-1 and EET are organized hierarchically and are inextricably linked forming a functionally-inter-related module in which HO-1 and EET work in concert to activate key protective systems, including adiponectin and downstream signaling molecules (AKT, AMPK), rendering the vascular endothelium resistant to injurious stimuli;consequently, a deficiency in one of these protective systems contributes to the manifestation of vascular injury in obesity. The major goal is to determine the optimum conditions for enhanced vascular resistance by focusing on the HO-1-EET module as a critical protective mechanism against injury-mediated vascular dysfunction. These are complex studies that require a sophisticated approach. Therefore, we assembled a battery of genetically modified mice (HO-1-/-, HO-1, HO-2-/-, EC-SOD-/-, APN-/-, sEHKO, HO-1-Tg, EET-Tg, and APN-Tg) and developed a lentiviral gene transfer strategy to provide loss and gain of functions;these together with highly specific probes (siRNAs) and distinct pharmacological agents (EET agonists/antagonists, enzymatic inhibitors) will provide the necessary tools for assessing the cause-and-effect relationship and carrying out a mechanistic analysis. We also developed a multifaceted approach to assess the vitality and functionality of the vascular endothelium. The data generated should provide solid information of how the HO-1-EET axis influences the control of the vascular phenotype that is responsible for vascular protection as well as the framework for translational clinical research to both treat and prevent vascular disease that results from endothelial dysfunction.

Public Health Relevance

Obesity and vascular dysfunction are major contributors to cardiovascular disease which remains a major cause of morbidity and mortality in the United States and places a significant economic burden upon society, about 100 billion dollars a year. This proposal seeks to understand the development of vascular disease from risk factors including hyperlipidemia, hypertension, obesity and the metabolic syndrome, but more importantly, to elucidate the mechanism necessary to preserve the vascular endothelium.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Ketchum, Christian J
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University of Toledo
Schools of Medicine
United States
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