Inflammation is a causative factor in most major cardiovascular diseases, including atherosclerosis, hypertension, acute respiratory distress syndrome (ARDS), diabetes, retinopathy and cancer. While glucocorticosteroids possess strong anti-inflammatory activity, their immunosuppressive and catabolic side-effects restrict their wide-spread use to only severe circumstances. Conversely, single-target anti-inflammatory agents (e.g., COX inhibitors) lack serious side effects but are void of broad-spectrum anti-inflammatory activity. Clearly, the availability of multi-targeted, strong anti-inflammatory agents with limited side effects would be of great significance in the prevention and management of cardiovascular disease. Emerging data suggest that heat shock protein 90 (hsp90) inhibitors may fit this profile. Recently, we demonstrated that pretreatment with either of two hsp90 inhibitors dramatically protects septic mice by greatly prolonging survival, reducing or abolishing systemic and end organ inflammation, attenuating capillary hyper-permeability and restoring normal end organ function. Preliminary data further suggest that these hsp90 inhibitors prevent as well as restore endothelial hyper-permeability induced by direct application of any of several pro-inflammatory mediators, in culture. The mechanism(s) behind these effects remain unclear. Since hsp90 inhibitors have recently completed Phase I and II trials for cancer, demonstrating low incidence and severity of side effects, they represent an exciting new possibility as clinically useful anti- inflammatory drugs. The purpose of this application is to investigate this possibility by exploring a key mechanism behind the anti-inflammatory effects of hsp90 inhibitors. Our overall hypothesis is that the anti-inflammatory effects of hsp90 inhibitors are largely due to their selective multi-targeting and inhibition of hsp90-associated pp60c-src, GSK-32 and I:K1 in inflamed tissues, leading to reduced pp60c-src-dependent formation of endothelial actin stress fibers, reduced GSK-32-dependent tau phosphorylation and microtubule depolymerization, thus preventing and repairing the endothelial barrier dysfunction associated with inflammation. The additional targeting and inhibition of I: 1 function also contributes to reduce NF: B function. Together, these actions reduce inflammation, prevent organ failure and restore major organ function. We will test this hypothesis in two mouse models of inflammation, an acute (i.p. LPS) and a chronic (type 2 diabetes exhibited by Leprdb mice) model. Given the persistent high mortality from cardiovascular disease, the possibility of quickly translating into clinical practice novel anti-inflammatory drugs should be appealing and of high priority.
This proposal aims to uncover the mechanisms behind the recently demonstrated anti-inflammatory effects of inhibitors of heat shock protein 90. Because these drugs have finished Phase II clinical trials and exhibit low side effects translation of these findings from these studies in cardiovascular disease should be expeditious.
|Thangjam, Gagan S; Dimitropoulou, Chistiana; Joshi, Atul D et al. (2014) Novel mechanism of attenuation of LPS-induced NF-*B activation by the heat shock protein 90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin, in human lung microvascular endothelial cells. Am J Respir Cell Mol Biol 50:942-52|
|Joshi, Atul D; Dimitropoulou, Christiana; Thangjam, Gagan et al. (2014) Heat shock protein 90 inhibitors prevent LPS-induced endothelial barrier dysfunction by disrupting RhoA signaling. Am J Respir Cell Mol Biol 50:170-9|
|Barabutis, Nektarios; Handa, Vaishali; Dimitropoulou, Christiana et al. (2013) LPS induces pp60c-src-mediated tyrosine phosphorylation of Hsp90 in lung vascular endothelial cells and mouse lung. Am J Physiol Lung Cell Mol Physiol 304:L883-93|
|Intapad, S; Dimitropoulou, C; Snead, C et al. (2012) Regulation of asthmatic airway relaxation by estrogen and heat shock protein 90. J Cell Physiol 227:3036-43|
|Zhang, Fengxue; Snead, Connie M; Catravas, John D (2012) Hsp90 regulates O-linked ýý-N-acetylglucosamine transferase: a novel mechanism of modulation of protein O-linked ýý-N-acetylglucosamine modification in endothelial cells. Am J Physiol Cell Physiol 302:C1786-96|
|Antonov, Alexander S; Antonova, Galina N; Fujii, Makiko et al. (2012) Regulation of endothelial barrier function by TGF-ýý type I receptor ALK5: potential role of contractile mechanisms and heat shock protein 90. J Cell Physiol 227:759-71|
|Chen, Feng; Pandey, Deepesh; Chadli, Ahmed et al. (2011) Hsp90 regulates NADPH oxidase activity and is necessary for superoxide but not hydrogen peroxide production. Antioxid Redox Signal 14:2107-19|
|Sun, Xutong; Fratz, Sohrab; Sharma, Shruti et al. (2011) C-terminus of heat shock protein 70-interacting protein-dependent GTP cyclohydrolase I degradation in lambs with increased pulmonary blood flow. Am J Respir Cell Mol Biol 45:163-71|