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.