Abstract 1329: Intramuscular Gene Transfer of Human Sonic Hedgehog Ameliorates Monocrotaline-induced Pulmonary Hypertension in Rats
Sonic hedgehog (Shh) is a critical regulator for embryonic organ development. We have previously demonstrated that Shh has a favorable effect on the recovery of acute and chronic myocardial ischemia via upregulating multiple favorable cytokines, including angiogenic factors, from fibroblasts. Pulmonary hypertension (PH) is a progressive disease characterized by increasing pulmonary vascular resistance resulting from narrowing or loss of microvasculature. Angiogenic gene or cell transfer have been reported to result in favorable outcome in certain models of PH. Accordingly, we investigated whether in vivo gene transfer of human Shh ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats.
Method and Results: We found that the Shh receptor patched-1 is abundantly present in lung fibroblasts. Adenovirus mediated expression of a soluble, secreted form of human Shh (Ad-Shh) or control gene (Ad-LacZ) was delivered IM in both femoral quadriceps muscles. Both Shh receptor patched-1 and transcriptional factor Gli were upregulated in the lung tissue, revealing that the Shh pathway was upregulated in lung tissue after remote Shh gene delivery. Three weeks after MCT injection, Ad-Shh significantly attenuated MCT-induced pulmonary hypertension (56.0±6.0mmHg vs. 79.3±5.5mmHg, P<0.05). Right ventricular weight was significantly decreased 3 wk after Ad-Shh injection (0.33±0.03g vs. 0.48±0.01g, P<0.01). Histologically, Ad-Shh inhibited the increase in medial wall thickness of peripheral pulmonary arteries that resulted from MCT injection (31±6% vs. 44±6%, P<0.01). Quantitative RT-PCR revealed that Shh increased Gli, VEGF, SDF-1, angiopoietin-1 and -2 expression in cultured rat lung fibroblasts in a dose dependent manner.
Conclusion: These data demonstrate that intramuscular gene transfer of secreted human Shh inhibits the progression of disease in experimental pulmonary hypertension by a mechanism involving protection against pulmonary vascular remodeling. Further, these findings imply that a strategy to preserve pulmonary microvascular integrity can have significant physiologic impact in pulmonary hypertension.