Abstract 16855: Kruppel-Like Factor 5 is Implicated in the Etiology of Pulmonary Arterial Hypertension.
Similarly to cancer, pulmonary arterial hypertension (PAH) is characterized by increased pulmonary artery smooth muscle cells (PASMCs) proliferation and decreased apoptosis. Those phenotypicaly altered PASMCs will cause an obstruction of the pulmonary arteries luminal space. In time this obstruction will lead to a hypertrophy of the right ventricle, and ultimately to the death of the patient. The transcription factor Kruppel-Like Factor 5 (KLF5) is involved in the transcriptional regulation of the pro-proliferative gene cyclin B1 and the anti-apoptotic gene survivin both of which are upregulated in PAH. We hypothesized that KLF5 plays a major role in the pathogenesis of PAH. KLF5 is over expressed (qRT-PCR and immunoblot) in PAs of both PAH patients (n=5) and PAH-rats (monocrotaline injected n=10) compare with healthy PAs. The upregulation of KLF5 is dose-dependently mediated by circulating pro-PAH factors including PDGF, IL-6, and ET-1 as healthy-PASMC exposed to increasing doses of pro-PAH factors showed a significant increase in KLF5 expression (qRT-PCR and immunoblot n=5; p<0.05). KLF5 inhibition using siRNA showed that KLF5 upregulation in PAH-PASMC accounts for both proliferation (FLUO-3; PCNA and Ki-67; n=150, p<0,05) and resistance to serum starvation-induced apoptosis (TMRM; annexinV and TUNEL; n=150, p<0,05). The decrease in the proliferation/apoptosis ratio is caused by the KLF5-dependent inhibition of both cyclin B1 (pro-proliferative (n=3, p<0.05)) and survivin (anti-apoptotic; n=3, p<0.05). In vivo, preliminary data showed that KLF5 inhibition (nebulized siRNA) in rats injected by monocrotaline (n=5) decreases mean PA pressure by 25 %, PA wall thickness by 30% and RV/LVS by 32%. In conclusion, KLF5 repression leads to a phenotypic reversal of PAH via the inhibition of both cyclin B1 and the proto-oncogene survivin. Our findings support a role of KLF5 in the etiology of PAH.
- © 2010 by American Heart Association, Inc.