Release Date: 11.01.2012
Rajamma Mathew, MD and her research group have been studying the role of caveolin-1 expression during the progression of pulmonary hypertension.
Before the onset of PH in rats with monocrotaline (MCT)-induced PH, the progressive loss of endothelial caveolin-1 is associated with the reciprocal activation of PY-STAT3, and increased Bcl-xl (proliferative and anit-apoptotic factors). Other endothelial membrane proteins (PECAM-1, Tie2, sGC) are also lost indicating extensive endothelial membrane damage. Rescuing caveolin-1 inhibits proliferative pathways and attenuates PH.
Endothelial damage is progressive. By 2 wks post-MCT, cytosolic proteins are also lost, accompanied by eNOS uncoupling and superoxide generation. By 3-4 wks eNOS expression is significantly reduced with normalization of superoxide generation. At 4 wks post-MCT, 29% of small arteries exhibit loss of von Willebrand Factor (vWF), and 70% of these arteries exhibited enhanced expression of caveolin-1 in smooth muscle cells(SMC).
The importance of caveolin-1 in PH is further supported by a recent report from Dr. Mathew’s group of a child who presented with severe PH two years after having made a complete clinical recovery from acute respiratory distress syndrome (ARDS). Lung biopsy revealed loss of endothelial caveolin-1 and vWF, associated with enhanced caveolin-1 expression in SMC. Subsequently he developed neointima and had a rapid downhill course.
Based on these results, Dr. Mathew's group hypothesizes that the endothelial damage is progressive and the loss of vWF indicates extensive damage/loss of endothelial cells, which may expose SMC to direct pressure/stress, leading to enhanced expression of caveolin-1 and possible translocation in SMC membrane. Caveolin-1 in SMC becomes proliferative, participating in cell proliferation, cell migration and worsening of disease.
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