Pulmonary arterial hypertension (PAH) is a non-curable chronic lung disease characterized by progressive increase in pulmonary arterial pressure leading to right ventricular (RV) heart failure. PAH is associated with inflammation and excessive proliferation of pulmonary artery smooth muscle cells and endothelial cells leading to severe pulmonary vascular remodeling. Interestingly, like in other inflammatory diseases such as atherosclerosis, it has been found that the levels of oxidized fatty acids such as hydroxyeicosatetraenoic acids (HETEs) and hydroxyoctadecadienoic acids (HODEs) are upregulated in the lungs from patients with PAH as well as in hypoxic rats with pulmonary hypertension (PH). We recently discovered that the levels of HETEs and HODEs are also robustly elevated in the plasma of PAH patients and in rats with PH. We also discovered that miR193, a miRNA which targets lipoxygenase (LOX) enzymes involved in the production of oxidized fatty acids, is significantly downregulated in the lungs and plasma of PAH patients and in two experimental animal models of PH. Overexpression of miR193 in the lungs rescued pre-existing PH in rats and mice highlighting the therapeutic role of miR193 in reversing pulmonary vascular remodeling. To further examine the role of oxidized fatty acids in development of PH, we placed wild type mice on 15-HETE diet for 3 weeks and we found that 15- HETE containing is sufficient to trigger PH. We hypothesize that HETEs and HODEs may play a causal role in PH. Our preliminary results in the lungs of mice on 15-HETE diet also show: i) levels of miR193 were significantly reduced; ii) ED1-positive inflammatory macrophage/monocytes were increased; and iii) expression of interlukin-17 receptor D (IL17-RD), which is a target of miR193, is significantly increased. This proposal has three arms: i) Mechanistic arm to test the hypothesis that 15HETE diet alone is sufficient to induce PH in WT mice by regulating miR193 and its targets through transcription factor RXR-a; ii) Diagnostic arm to determine whether plasma oxidized fatty acids together with miR193 could serve as biomarker panel for PAH; and iii) Therapeutic arm to examine the role of miR193 for reversal of adverse vascular remodeling in PAH patients.
Aim 1 will determine the role of RXR?/miR193/LOX pathway in development of PH induced by 15-HETE diet;
Aim 2 will determine the role of miR193 targets IL-17RD and IGFR1 in development of PH induced by 15-HETE diet;
and Aim 3 will examine the clinical relevance of oxidized fatty acids and miR193 in PAH patients. This proposal will provide for the first time pivotal information on the role of pro-inflammatory oxidized fatty acids and miR193 that modulate their levels in the regulation and development of pulmonary hypertension.
Despite recent progress in medical therapy, current treatments for PH can only improve patients' symptoms temporarily, and gradual deterioration in their condition often necessitates a lung transplant. This proposal will investigate the role of oxidized lipids and microRNA-193 in the pathogenesis of PH. We will delineate novel underlying mechanisms and exploit our mechanistic experimental design to develop new treatments and biomarkers for this complex disease.
| Umar, Soban; Cunningham, Christine M; Itoh, Yuichiro et al. (2018) The Y Chromosome Plays a Protective Role in Experimental Hypoxic Pulmonary Hypertension. Am J Respir Crit Care Med 197:952-955 |
| Umar, Soban; Partow-Navid, Rod; Ruffenach, Gregoire et al. (2017) Severe pulmonary hypertension in aging female apolipoprotein E-deficient mice is rescued by estrogen replacement therapy. Biol Sex Differ 8:9 |
