Progression and regression of pulmonary vascular disease related to smooth muscle cell apoptosis, S100A4/Mts1 and fibulin-5.
Published: 2005
Language: eng
Number of pages: 267
Description: Our laboratory previously reported reversal of PAH in rats by elastase inhibitor-induced SMC apoptosis. The proposed mechanism of apoptosis was related to MMP repression and subsequent loss of alphavbeta 3 integrin and EGFR signaling. This suggests that blockade of these downstream effectors might also induce regression of PAH. We confirmed that MMP inhibition (SC-080) or alphavbeta3 integrin blockade (Cilengitide) mediates SMC apoptosis and regression of medial hypertrophy in PA organ culture and documented similar results with EGFR TKI. We then induced PAH in rats by monocrotaline injection and, at day 21, began a two-week treatment with SC-080, Cilengitide, or the EGFR inhibitor PKI166. No vehicle or Cilengitide-treated animal survived beyond two weeks. SC-080 treatment resulted in 44% survival but without evidence of disease regression. PKI166 therapy, however, resulted in 78% and 54% survival in daily and 3x/week-treated animals respectively. Long-term survival, 4 weeks after treatment cessation, was associated with reduced PAH and RVH, and regression of vascular remodeling. Blockade of EGFR signaling, therefore, may be a novel strategy to reverse progressive PAR The ability to induce regression of human pulmonary vascular lesions, however, relies on similarities between experimental models and clinical tissue. Interestingly, transgenic mice over-expressing S100A4/Mts1 occasionally develop severe PVD. To determine if this phenotype could be induced consistently we exposed S100A4/Mts1 and control C57Bl/6 mice to two weeks of chronic hypoxia. S100A4/Mts1 mice had greater RVSP and RVH at baseline, which increased further with chronic hypoxia and was sustained after three months' recovery in room air. These findings correlated with a heightened response to acute hypoxia and impaired vasodilatation with NO or oxygen. S100A4/Mts1 mice also had reduced ventricular elastance and decreased CO. The S100A4/Mts1 mice did not develop more severe PVD with chronic hypoxia but showed impaired regression upon return to room air. Microarray analysis of lung tissue identified an increase in expression of fibulin-5, a matrix component necessary for elastin fiber assembly, and induced by S100A4/Mts1. Fibulin-5 was localized to PAs and associated with thickened elastic laminae. This feature could underlie attenuation of pulmonary vascular changes in response to elevated pressure, as well as impaired reversibility.
Notes: Thesis (Ph.D.)--University of Toronto, 2005.

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Source: Dissertation Abstracts International, Volume: 66-06, Section: B, page: 3051.