An RV-T cell axis in pulmonary hypertension

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Paulin, Roxane (Department of Medicine, Laval University)
Mentor: Provencher, Steeve
Co-Mentor: Michelakis, Evangelos D.
Network Affiliation: Canadian Vascular Network
1. The health problem/issue
In patients with high blood pressure in the lungs (pulmonary hypertension PHT), the small vessels permitting the blood to be re-oxygenated in the lungs are obstructed. Similarly to the pressure of water going through an obstructed pipe, the pressure of the blood going through theses clogged arteries is increased. The right chamber of the heart needs therefore to push harder the blood in these vessels to keep the same efficiency of oxygenation. The right chamber of the heart is a muscle and becomes bigger to gain efficacy. This causes many symptoms such as shortness of breath. Eventually, the right heart will not be able to compensate the increase and pressure and will fail, causing patient death. In contrast to the many therapies that improve the function of the left chambers of the heart no therapy is available for the failure of the right chambers. Patients with PHT also have evidence of inflammation in their blood, similar to patients suffering from infections. Although we know that this inflammation is a worsening factor, we do not know its cause in PHT. We propose to study a completely new mechanism by which the right chamber of the heart can activate inflammation in the blood. Based on our recent work, we propose that the right heart in PHT produce lower amounts of a molecule called miR-208, and that the decreased levels of that molecule cause activation of inflammation in a manner similar to what viruses do.
2. The objectives
The overall objective is to study whether the right heart secrete circulating molecules that can influence inflammation. Especially, we will study whether miR-208 protects against inflammation and whether its absence promotes it.
3. The approach
We will use first inflammatory cells isolated from rat spleen and we will expose them to a synthetic miR-208 activator or inhibitor and will evaluate whether they promote the survival and the multiplication of inflammatory cells, ultimately leading to a response similar to inflammatory response. miR-208 is usually encapsulated and protected in small vesicle that circulate in the blood stream and that can be up taken by the cells of the immune system. We will therefore study if encapsulated miR208 injected to rats with PHT has the potential to decrease inflammation and improve the disease. We will also evaluate if the level of miR208 in the blood of patient with PHT can predict the level of inflammation they suffer from and the health status of their right heart. This will facilitate the potential future use of our findings into clinical practice.
4. The unique factors
In this program, we hypothesize for the first time that the decline of the right heart function is implicated in inflammation, inflammatory cells activation. The origin and role of inflammation in PHT are unclear. High blood pressure in PHT originates in part from the multiplication of cells in the wall of the vessels resulting in vessel obstruction. Inflammation might be activated as a mechanism of repair and that, in absence of successful repair, keeps progressing. However, in animal models of PHT, while vessels obstruction slows down in late stages of the diseases, inflammation keeps increasing. Our lab and others have already demonstrated the role of inflammation in the decline of right chambers health, however this is the first time that the opposite is envisaged.
5. How the project is relevant to the objectives of the initiative
Dysfunctions of the right heart are not well understood, and globally understudied compared to dysfunction of the left heart. Right heart deterioration is usually really fast, happening in about 3-5 years while it can take decades for the left heart to fail. We are not currently able to predict when a right heart is about to fail. This research proposal aim to increase the knowledge on mechanisms that drives their deterioration in order to be able to predict failure and potentially to reverse it. The lack of any right heart-specific therapies results in the very high mortality rate that characterizes many diseases including PHT. This work may enhance our understanding of right heart failure, our ability to predict it and eventually reverse it.
6. The impact
Despite advances in research and treatment, heart disease and stroke remain a leading cause of death in Canadians'. 9 in 10 Canadians have at least one risk factor for heart disease or stroke. Heart disease and stroke is also the number 1 killer of women. Our work, particularly dedicated to cure and improve the condition of patients suffering from heart disease is obviously in complete agreement with HSF’s mission. Our work will help the diagnosis, the prediction of the outcome and have the potential to enhance the development of new treatments. We believe that our work will change minds further regarding the right heart and considering it as an active organ during failure.