Local Inhibition of HSP90 to Prevent Intimal Hyperplasia after Balloon Injury
Technical Report,30 Sep 2016,29 Sep 2017
Research Foundation of the State University Syracuse United States
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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 IHafter 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 less toxicity and are in clinical trials for cancer therapy.
- Medicine and Medical Research