The pathogenesis of hypoxia-induced pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling contributingto increased pulmonary vascular resistance leading to right heart failure. These responses are characterized by functional changes in resident vascular wall cells including smooth muscle (SMC), endothelial,and fibroblast, as well as recruitment of circulating progenitor and inflammatory cells. Our preliminary data indicatethat hypoxia leads to rapid activation of Akt in SMC of the lung vasculature. PTEN is a negative regulator of PI3-kinase/Akt/mTOR signaling, and an inhibitor of SMC proliferation. We have shown that SMC-specific, targeted PTEN mutant mice (PTEN KO) spontaneously develop pulmonary hypertension. PTEN KO mice also exhibit increased perivascular and serum chemokine levels, increases in circulating progenitor cells, and trafficking of progenitor cells to major vessels and the lung. Work by other investigators in this PPG demonstrated that rosiglitazone, a specific activator of the nuclear receptor PPARy, attenuates hypoxia-induced pulmonary vascular remodeling. In other systems, the ability of PPARy to inhibit cell proliferation and regulate anti-inflammatory responses is mediated, in large part, through the upregulation of PTEN expression and/or activity. Based on these collective observations, we hypothesize that inactivation of PTEN in pulmonary arterial SMC will induce severe PAH in response to chronic hypoxia. This response will be mediated by direct effects on SMC hyperplasia as well as the production of chemokines by SMC which will be involved in the recruitment of progenitor/pro-inflammatory cells and may also act in an autocrine fashion on the SMC themselves. Conversely, activation of PPARy will inhibit hypoxia-induced pulmonary vascular remodeling at least in part through the upregulation of PTEN. This project will employ both in vivo and in vitro approaches to test this model.
Two specific aims are proposed.
Aim l will use a novel, tampxifen-inducible PTEN knockout mouse model to examine the effects of SMC-specific deletion of PTEN in mice on chemokine- induced SMC hyperplasia and recruitment of progenitor and inflammatory cells during hypoxia-induced pulmonary vascular remodeling. This model will allow fate-mapping of medial SMC and bone marrow- derived progenitor cells during the pathogenesis of PAH, providing clear information regarding the contributions of these cells in pulmonary vascular remodeling. In vitro studies will use shRNA silencing of PTEN in pulmonary artery SMC to define downstream effectors mediating these responses.
Aim 2 will employ an analogous strategy to specifically delete PPARy in vivo and compare responses with PTEN deficient mice. In vitro experiments will establish the role of PTEN in mediating the effects of PPARy. Finally, the role of PTEN in mediating the protective effects of rosiglitazone and pioglitazone, two well- characterized PPARy activators, will be examined.
The molecular pathways mediating hypoxia-induced PAH involve multiple cell types. This project is designed to specifically examine the contribution of SMC to this process. Novel mouse models in which signaling pathways can be manipulated in a time-dependent fashion specifically in SMC will define the role of SMC. In vitro approaches will delineate molecular pathways controlling growth, phenotypic modulation and cytokine production by these cells. Pharmacological agents regulating these pathways represent novel therapeutic agents for treatment and prevention of PAH.
|Keller, Amy C; Knaub, Leslie A; Miller, Matthew W et al. (2015) Saxagliptin restores vascular mitochondrial exercise response in the Goto-Kakizaki rat. J Cardiovasc Pharmacol 65:137-47|
|Ostriker, Allison; Horita, Henrick N; Poczobutt, Joanna et al. (2014) Vascular smooth muscle cell-derived transforming growth factor-? promotes maturation of activated, neointima lesion-like macrophages. Arterioscler Thromb Vasc Biol 34:877-86|
|Geary, Kate; Knaub, Leslie A; Schauer, Irene E et al. (2014) Targeting mitochondria to restore failed adaptation to exercise in diabetes. Biochem Soc Trans 42:231-8|
|Stearman, Robert S; Cornelius, Amber R; Lu, Xiao et al. (2014) Functional prostacyclin synthase promoter polymorphisms. Impact in pulmonary arterial hypertension. Am J Respir Crit Care Med 189:1110-20|
|El Kasmi, Karim C; Pugliese, Steven C; Riddle, Suzette R et al. (2014) Adventitial fibroblasts induce a distinct proinflammatory/profibrotic macrophage phenotype in pulmonary hypertension. J Immunol 193:597-609|
|Lehman, Allison M B; Montford, John R; Horita, Henrick et al. (2014) Activation of the retinoid X receptor modulates angiotensin II-induced smooth muscle gene expression and inflammation in vascular smooth muscle cells. Mol Pharmacol 86:570-9|
|Wang, Daren; Zhang, Hui; Li, Min et al. (2014) MicroRNA-124 controls the proliferative, migratory, and inflammatory phenotype of pulmonary vascular fibroblasts. Circ Res 114:67-78|
|Horita, Henrick; Furgeson, Seth B; Ostriker, Allison et al. (2013) Selective inactivation of PTEN in smooth muscle cells synergizes with hypoxia to induce severe pulmonary hypertension. J Am Heart Assoc 2:e000188|
|Gupta, Vivek; Gupta, Nilesh; Shaik, Imam H et al. (2013) Liposomal fasudil, a rho-kinase inhibitor, for prolonged pulmonary preferential vasodilation in pulmonary arterial hypertension. J Control Release 167:189-99|
|Reusch, Jane E B; Bridenstine, Mark; Regensteiner, Judith G (2013) Type 2 diabetes mellitus and exercise impairment. Rev Endocr Metab Disord 14:77-86|
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