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Acute caspase inhibition attenuates progressive vascular remodeling in established Pulmonary Arterial Hypertension
Author(s) -
Happé C M,
Szulcek R.,
Rol N.,
Schalij I.,
Westerhof N.,
VonkNoordegraaf A,
De Man F.S.,
Nieuwe Amerongen G.P.,
Bogaard H.J.
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.662.11
Subject(s) - apoptosis , cd31 , lung , vascular remodelling in the embryo , chemistry , endothelium , pulmonary hypertension , caspase 3 , medicine , vascular resistance , endocrinology , cancer research , hemodynamics , angiogenesis , programmed cell death , biochemistry
In pulmonary arterial hypertension (PAH) a phenotypic switch of the endothelium results in exuberant cell growth and vascular remodeling. Recent animal models of PAH show a high cell turnover with coexisting high rates of apoptosis and proliferation. In vitro experiments suggest that high shear stress induces a loss of PAH patient derived microvascular endothelial cells (MVEC). We tested whether an impaired response to increased shear stress and ongoing apoptosis are involved in vascular remodeling in PAH.
Rats with progressive PH were treated for 2 weeks with the pan‐caspase inhibitor Z‐Asp. PAH patient derived MVECs were treated with Z‐Asp and subjected to increased levels of fluid shear stress to simulate the hemodynamics of the PAH lung.
Analysis revealed a significant decrease in cleaved caspase 3 positive cells in lung endothelial cells (0.6±0.1 vs. 0.2±0.1, p=0.02) and smooth muscle cells (2.2±0.2 vs. 1.2±0.5, p=0.02). A reduction in pulmonary vascular resistance (0.9±0.2 vs. 0.5±0.1, p=0.01) with Z‐asp was associated with a decrease in intima thickness (24±4 vs. 14±2, p=0.001). Detailed analysis showed a decrease in the proliferative marker PCNA in endothelial cells (1.5±.4 vs. 0.8±0.2, p=0.05). Mechanistically, Z‐Asp in MVECs improved shear adaptation and prevented shear‐induced cell loss by restoring protein surface levels of the mechanosensor CD31.
In conclusion, we showed that caspase inhibition in experimental PAH attenuates vascular remodeling by restoration of endothelial shear adaptation and apoptosis reduction. Our data suggests that new PAH treatment concepts should consider apoptosis prevention instead of induction.