TARGETING ACTIVATED MINERALOCORTICOID RECEPTOR IN PULMONARY ARTERIAL HYPERTENSION: A translational approach towards treatment – TAMIRAH
Pulmonary Arterial Hypertension (PAH) is a frequently lethal condition without cure. The current therapies remain essentially palliative and do not reverse the progressive pulmonary vascular obstruction leading to right ventricular heart failure. Therefore, new therapies are urgently needed for this life-threatening disease. One of the central unanswered questions in PAH pathogenesis relates to the mechanisms underlying the accumulation of vascular wall cells and perivascular infiltration of inflammatory cells, two key mechanisms leading to pulmonary vascular remodeling.
Interestingly, mineralocorticoid receptor (MR), a steroid receptor belonging to the nuclear receptor superfamily of transcription factors, exerts a direct role in proliferative, pro-inflammatory and remodeling vascular responses. MR can be activated either by aldosterone through a classical pathway, or by a direct and rapid action of oxidative stress and/or angiotensin (Ang)II, through AT(1) receptor binding in a non-classical pathway in heart, lung and vasculature. Importantly, we have discovered, in idiopathic PAH (iPAH), that dysfunctional pulmonary endothelium is a local abnormal source of AngII and that pulmonary artery smooth muscle cells (PA-SMC) overexpress AT1 receptor. This observation is of interest since these abnormalities could lead to an aberrant MR activation in PA-SMC in iPAH and partly explain their abnormal hyperproliferative, anti-apoptotic and pro-inflammatory phenotype. Although this MR activation represents an attractive therapeutical target, the translational relevance of targeting activated MR in iPAH remains an opened relevant question.
Our project seeks to better understand the contribution of the activated MR in PA-SMC and their precursor pericytes (PC) in PAH regarding their accumulation within the vascular wall and their capability to locally recruit inflammatory cells. In addition, we will determine if this pathway could be rapidly amenable to treatment modalities for PAH.
To address these two issues, we have recently performed in situ and in vitro studies to evaluate MR activation in PA-SMC from control and iPAH patients. Our preliminary data underscore a 2- to 3-fold increase in MR expression (mRNA and protein) in PA-SMC and PC of iPAH patients when compared with control specimens. Importantly, we also recently observed that mice overexpressing MR (hMR+ mice), generated by Partner 2, develop spontaneous PAH in room air with increased right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), percentage of muscularized pulmonary arterioles and levels of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 versus wildtype (WT) littermates (Fig.1).
Therefore, our objectives are now to address 3 complementary questions:
1. Does over-activation of MR signaling contribute to aberrant cell accumulation within the pulmonary vasculature in PAH?
2. Does over-activation of MR signaling in PA-SMC / PC lead to accumulation and polarization of alveolar macrophages toward the M2 phenotype in PAH?
3. Could we use MR antagonists in order to potentiate the beneficial effects of the current PAH specific therapies?
Although previous studies have suggested a role for deregulation of the MR signaling pathway in the development/progression of PAH, several questions remain to move forward to clinical trials, particularly regarding the role of MR in the acquisition and/or maintenance to the altered PA-SMC and PC phenotypes, in the increased perivascular immune cell infiltration and activation observed in PAH. We believe that our project could hence determine if this pathway could be rapidly amenable to treatment modalities for PAH and serve as an important starting point in the clinical evaluation of next generation MR antagonists, whose efficacy will be evaluated against the development/progression of experimental PAH in our in vitro and in vivo preclinical PAH models.
Monsieur Christophe Guignabert (INSERM UMR_S 999 - Hypertension artérielle pulmonaire, pathophysiologie et innovation thérapeutique)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
INSERM INSERM UMR_S 999 - Hypertension artérielle pulmonaire, pathophysiologie et innovation thérapeutique
INSERM UMR_S 1185 INSERM UMR_S 1185 - Signalisation hormonale, physiopathologie endocrinienne et métabolique
Help of the ANR 551,440 euros
Beginning and duration of the scientific project: October 2016 - 42 Months