Vascular Insulin Signaling and Pulmonary Arterial Hypertension

Ussher, John (Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta)
Mentor: Seubert, John M.
Network Affiliation: Canadian Vascular Network
1. The health problem/issue
Pulmonary arterial hypertension is a devastating form of heart/lung disease involving a massive multiplying of cells in the blood vessels of the lungs, which decreases blood flow and normal oxygenation, causing death in about 50% of patients by year 3 following diagnosis as a result of heart failure (a heart disease in which the heart cannot pump blood to the rest of the body normally). Interestingly, obese people are at an increased risk of developing pulmonary arterial hypertension, but it is unknown as to why this is the case. 
2. The objective
Insulin is a hormone that causes sugar from the blood to be transported into organs (e.g. heart, muscle, liver, etc.) to provide those organs with the energy they need to work properly. Interestingly, increased metabolism of sugar in lung blood vessels has been shown to be partly responsible for causing pulmonary arterial hypertension. Because insulin levels in the blood are increased in obese patients, our research proposal aims to understand the role of insulin in controlling sugar metabolism in lung blood vessels of these patients, and whether blocking insulin’s ability to enhance sugar metabolism in lung blood vessels may be an exciting new way to treat pulmonary arterial hypertension.
3. The approach
My laboratory will grow cells isolated from lung blood vessels in an environment similar to that seen in obese patients (high sugar and fat levels in the blood) and examine whether insulin is able to increase sugar metabolism in these cells. Additionally, my laboratory will have obese mice live in low oxygen conditions to mimic pulmonary arterial hypertension in humans. A group of these obese mice will be genetically modified in a manner that blocks insulin’s ability to increase sugar metabolism in their lung blood vessels, and we will monitor the progression of pulmonary arterial hypertension.
4. The unique factors
Our research is unique because it suggests a potential paradox doctors may face when caring for obese patients. Indeed, drugs are usually designed to increase insulin action in obese patients to treat their diabetes. However, we hypothesize that blocking insulin action will be beneficial for obese patients with pulmonary arterial hypertension. Therefore, increasing insulin action in obese patients may improve their diabetes but worsen their heart disease.
5. How the project is relevant to the objectives of the initiative
Our research is directly relevant to heart disease as our proposal is investigating how excessive insulin action in obese patients may increase their risk for pulmonary arterial hypertension.
6. The impact
If our hypothesis is correct, our research will suggest that new drugs should be developed that selectively block insulin action only in the lungs, which may significantly improve the health and quality of life of obese patients that also have pulmonary arterial hypertension.