Abstract 9519: Knockdown of TRPC1 Expression Markedly Attenuates Hypoxia-Induced Pulmonary Arterial Hypertension in a Murine Model: Advantage of Liposome-Mediated siRNA Delivery System
Background: We tested the hypothesis that Lipofectamine siRNA delivery to deplete transient receptor potential cation channel (TRPC)1 protein expression can suppresses hypoxia-induced pulmonary arterial hypertension (PAH) in mice.
Methods and Results: Adult male C57BL/6 mice (n=30) were equally divided into group 1 (normal controls), group 2 (hypoxia for 28 days), group 3 [hypoxia + Lipofetamine-delivered siRNA to knockdown TRPC1 (intra-tracheally administered on day 14 after hypoxia)]. By day 28, right ventricular blood pressure (RVSBP), number of muscularized arteries, RV and the lung weight were increased in group 2 than in group 1, and reduced in group 3 compared with group 2 (all p<0.001). Pulmonary crowded score showed similar pattern, whereas number of alveolar sacs exhibited an opposite pattern compared to that of RVSBP in the three groups (all p<0.0001). Protein expressions of TRPCs (1, 4, 6), HIF-1α, Ku-70, apoptosis (Bax, cleaved caspase 3, and PARP) and fibrosis (Smad3, TGF-β) and pulmonary mRNA expressions of inflammatory markers (MMP-9, TNF-α) was similar to, whereas protein expressions of anti-fibrosis (Smad1/5, BMP-2) and VEGF was opposite to the pattern of RVSBP (all p<0.01). Cellular markers of pulmonary DNA damage (γHA2X), repair (Ku-70), and smooth-muscle proliferation (Ki67) exhibited a pattern similar to that of RVSBP (all p<0.001). Pro-apoptotic mRNA expressions of (Bax, caspase 3) and hypertrophy (β-MHC) displayed a similar pattern, whereas sacromere length showed an opposite pattern compared to that of RVSBP in all groups (all p<0.001).
Conclusion: Lipofectamine siRNA delivery effectively knockdown PRTC1 expression, thereby attenuating PAH-associated RV and pulmonary arteriolar remodeling.
- © 2013 by American Heart Association, Inc.