title: Heme oxygenase-1 mediates the protective effects of rapamycin in monocrotaline-induced pulmonary hypertension.
abstract: Rapamycin inhibits the development and progression of vascular disease. We previously showed that rapamycin induces the cytoprotective protein, heme oxygenase-1 (HO-1), and more importantly, chemically inhibiting HO-1 blocked the antiproliferative actions of rapamycin. In this study, we evaluated whether HO-1 is required for the vascular protective effects of rapamycin in vivo using a rat monocrotaline-induced pulmonary hypertension model. Rats were exposed to monocrotaline with or without rapamycin and HO activity was altered using the chemical inhibitor, tin protoporphyrin or the inducer, cobalt protoporphyrin. We also evaluated possible mechanisms of rapamycin-dependent induction of HO-1, and how HO-1 mediates growth factor-dependent antiproliferative actions of rapamycin. Proliferation and cell cycle progression were examined in smooth muscle cells derived from both wild-type and HO-1 knockout (HO-1-/-) mice in response to growth factors and rapamycin. Similar to our previous findings in vitro, rapamycin induced HO-1 in rat lung. Rapamycin also inhibited the development of monocrotaline-induced pulmonary hypertension, and this protective effect was blocked with the addition of tin protoporphyrin. In addition, treatment with cobalt protoporphyrin resulted in a substantial protection in this model of pulmonary hypertension. Rapamycin induction of HO-1 was dependent upon a transcriptional event; however, it was not mediated through an altered redox state or mammalian targets of rapamycin inhibition. Unlike wild-type cells, the growth of HO-1-/- mouse aortic smooth muscle cells was not inhibited or cell cycle arrested in G1 in response to rapamycin. This study demonstrates that HO-1 is critical for the antiproliferative and vascular protective effects of rapamycin in vitro and in vivo in monocrotaline-induced pulmonary hypertension.
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, FL 32610-0296, USA.
authors.forename: Hailan
authors.initials: H
authors.lastname: Zhou
authors.forename: Hanzhong
authors.initials: H
authors.lastname: Liu
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Porvasnik
authors.forename: Naohiro
authors.initials: N
authors.lastname: Terada
authors.forename: Anupam
authors.initials: A
authors.lastname: Agarwal
authors.forename: Yanping
authors.initials: Y
authors.lastname: Cheng
authors.forename: Gary A
authors.initials: GA
authors.lastname: Visner
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D002453:Cell Cycle; D049109:Cell Proliferation; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D016686:Monocrotaline / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016686:Monocrotaline; D006419:Heme Oxygenase (Decyclizing); D020123:Sirolimus