View The Document

Accession Number:



Local Inhibition of HSP90 to Prevent Intimal Hyperplasia after Balloon Injury


Author Organization(s):

Report Date:



Peripheral arterial disease (PAD) remains a major threat to life and limb and represents a disabling and potentially fatal condition in the aging military and veteran population. Dyslipidemia is an important mechanism in the pathogenesis of PAD and the development of restenosis secondary to intimal hyperplasia (IH)after balloon angioplasty. IH is a complex process that begins by platelet activation, platelets then bind to the area of vascular injury releasing thrombospondin-1 (TSP-1) and platelet derived growth factor (PDGF). These in turn cause vascular smooth muscle (VSMC) migration into the area of injury where they begin to proliferate and produce extracellular matrix like hyaluronic acid (HyA). All of these processes clearly contribute to IH by regulating the arterial response to injury. Heat shock protein 90 (HSP90) is a molecular chaperone binds many signaling proteins regulating their final maturation. HSP90 is ubiquitously expressed and is important for normal cell function. However, aberrant activation of HSP90 can result in increased cell migration and proliferation. Inhibition of HSP90 has been in examined in states of aberrant cell growth such as cancer. The quintessential HSP90 inhibitor is the natural product geldanamycin, however, geldanamycin exhibits a relatively high toxicity. Several derivatives of geldanamycin have been created that have significantly lesstoxicity and are in clinical trials for cancer therapy.



File Size:





Distribution Statement:

Approved For Public Release

View The Document