Submission
| Title: | Activation Of The Mitochondrial Unfolded Protein Response (uprMt) Promotes Vascular Remodeling In Pulmonary Arterial Hypertension. |
| Presenter: | Arthur Ssendawula |
| Institution: | Indiana University Indianapolis |
| Authors: | A. Ssendawula, A. Snow, T. Mubuuke, R. F. Machado, A. Lockett |
Abstract
| Background/Significance/Rationale: | Pulmonary Arterial Hypertension (PAH) is a severe and progressive disease which results in death due to increased pulmonary vascular resistance that leads to right heart failure. Increased vascular resistance occurs as a result of pulmonary arterial smooth muscle cells (PASMCs) and endothelial cells (PAECs) undergoing changes in intracellular signaling that leads to a proliferative, apoptosis resistant phenotype that causes remodeling and occlusion of the pulmonary vasculature. We demonstrated that the sphingosine-1-phosphate (S1P)/sphingosine kinase 1(SPHK1) signaling pathway promotes vascular remodeling, that it is upregulated in PAH patients and that inhibition of S1P mitigates PAH in vivo. Preliminary data from our lab demonstrates that the mitochondrial unfolded protein response (UPRmt) is activated by the S1P pathway. Hence, we hypothesized that the UPRmt induces vascular remodeling to promote PAH development. |
| Methods: | Human PASMCs and PAECs were treated with S1P up to 6h or Lentiviral-Sphk1 was overexpressed for 48h at MOI 20. Western blotting was performed on whole cell extracts to assess regulation of the UPRmt pathway. Activation of UPRmt mediators was assessed by immunoblotting for mtHSP70, HSP60, ClpP and LonP1. The effect of UPRmt inhibition on proliferation was assessed by Western blotting for PCNA and Ki67 expression level. |
| Results/Findings: | Activation of the Sphk1-S1P signaling axis promoted activation of the UPRmt pathway as we observed increased expression of UPRmt pathway mediators (mtHSP70, HSP60, ClpP and LonP1). There was also an increase in vascular remodeling as expression of proliferation markers was elevated. Inhibition of the UPRmt using the mtHSP70 inhibitor, MKT-077, mitigated the increase in proliferation. |
| Conclusions/Discussion: | Aberrant regulation of mitochondrial function leading to activation of the UPRmt pathway promotes vascular remodeling. |
| Translational/Human Health Impact: | Currently, no therapeutic interventions exist to treat vascular remodeling in PAH. These studies suggest that pharmacological interventions targeting the UPRmt pathway may improve PAH outcomes. |
