Biomedical Engineering Reference
In-Depth Information
which might affect both the synthetic phenotype and contractile functions of
VSMCs. Pharmacological inhibition of either ACE or the AT1 receptor partially
reverses vascular dysfunction and normalized gene expression in miR-143/
145-deficient mice. Manipulation of miR-143/145 expression may offer a new
approach for influencing vascular repair and attenuating arteriosclerosis (Boettger
et al.
2009
). This important discovery will open the door to new avenues of inves-
tigation and potentially future therapies for restenosis following angioplasty.
Gene Therapy to Prevent Restenosis After Angioplasty
Some of the targets for gene-based therapies of restenosis are:
•
Prevention of thrombosis by inhibition of platelet effects and fibrin deposit.
•
Inhibition of cytokines which downregulate proliferation. This requires identifi-
cation of appropriate receptor antagonists.
Cytostatic approaches to block cell cycling.
•
•
Arterial regeneration by endothelial proliferation. The aim is to restore endothe-
lium, and intimal hyperplasia should be avoided.
Antiatherosclerotic gene transfer to reverse disease progression.
•
•
Adenovirus-encoded ribozyme to PDGF to inhibit neointima formation after
arterial injury.
Inhibition of various factors producing restenosis can be achieved by delivering
genes expressing dominant negative gene products. Included among such genes are
NO synthase, tPA, thymidine kinase, PGHS, and p21.
Prostacyclin (PGI2) is one of the most potent inhibitors of platelet activation,
secretion, and aggregation, as well as a potent vasodilator. Its biosynthesis in ves-
sel walls is catalyzed by phospholipase A2 (PLA2) prostaglandin H synthase
(PGHS). PGHS is severely inactivated during catalysis. At sites of vascular injury,
its quantity is further reduced and the capacity of PGI2 synthesis is compromised.
Adenoviral vectors have been used for direct delivery of PGHS-1 genes to enhance
the synthesis of vasoprotective molecules. The effectiveness of PGHS-1 transfer
in reducing the thrombosis and intimal hyperplasia was demonstrated by infusion
of Ad-PGHS through perforated catheters into balloon-injured pig carotid
arteries.
Ras protein is a transducer of mitogenic signals. Inhibition of ras should be use-
ful for therapy of vascular proliferative disorders. Ras inhibition by dominant nega-
tive mutants led to significant reduction of neointima formation after experimental
blood vessel injury in a rat model.
Retinoblastoma gene product (Rb) is present in arterial smooth muscle cells
(SMC) and inhibits cell proliferation. However, it is rapidly inactivated by phos-
phorylation. Adenovirus-mediated transfer of constitutionally active form of Rb at
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