Treatment strategies aimed at reducing adverse cardiac events in patients with diabetes have embraced both optimal medical therapy and interventional catheter based management but in doing so have exposed patients to new and poorly understood risks. Major advances in PCI and medical therapies have created a serious disconnect between the eagerness to use new medical devices such as drug eluting stents (DES) in combination with diabetic therapies such as PPAR3 agonists on the one hand and the understanding of how their underlying divergent therapeutic signatures might clinically interact on the other. Our preliminary data suggest that these treatment combinations may impair stent re-endothelialization due to molecular interactions between systemic therapies and locally eluted drug and may help to explain the increased risk of thrombotic complications seen in patients with diabetes receiving DES. ) The majority of DES using in clinical practice are designed to elute pharmacologic agents such as sirolimus that inhibit the mammalian target of rapamycin (mTOR), a member of the phosphatidylinositol kinase-related family of Ser/Thr kinase. Although animal studies have alluded to the fact that inhibitors of mTOR delay endothelial cell growth and recovery, the precise mechanisms are yet to be reconciled. The related lack of understanding of the functional attributes of commonly used anti-diabetic agents such as PPAR3 agonist in the presence of mTOR inhibitors is perhaps more critical from the standpoint of drug development. The central purpose of this proposal is to provide a better understanding of the cellular mechanisms required to inform treatment strategies in diabetic patients with coronary disease by delineating the cellular mechanisms by which mTOR inhibition delays endothelial regrowth, exploring the molecular basis for the relationship between mTOR and PPAR3, and determining the potential pathophysiological consequences and impact of this interaction on expression of VEGF and endothelial regrowth. More clearly defining the role of mTOR in endothelial recovery after stent placement as well as its precise relationship to the molecular targets of commonly used diabetes medications may help avoid clinical situations that further impair stent healing due to molecular interactions between eluted drug and systemic medications. In this proposal, we demonstrate in a relevant animal model of arterial healing that this type of interaction can have a significant impact on endothelialization after sirolimus eluting stent placement due to molecular interactions between PPAR3 agonists and the mTOR inhibitor sirolimus. The studies we propose will enable us 1) to define the impact of arterial wall mTOR inhibition in combination with PPAR3 agonists on stent re- endothelialization in a diabetic rabbit model;2) elucidate the relevant molecular mechanisms of mTOR to PPAR3 interactions and the ultimate pathophysiological impact on VEGF expression;and 3) delineate the exact mechanisms by which mTOR inhibitors delay stent healing.)

Public Health Relevance

Treatment strategies aimed at reducing adverse cardiac events in patients with diabetes mellitus have embraced both optimal medical therapy and interventional catheter based management but in doing so have exposed patients to new and poorly understood risks. Major advances in revascularization techniques and medical therapies have created a serious disconnect between the eagerness to use new medical devices such as drug eluting stents (DES) in combination with diabetic therapies on the one hand and the understanding of how their underlying divergent therapeutic signatures might clinically interact on the other. A better understanding of this relationship will improve treatment outcomes for patients with diabetes mellitus and coronary artery disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL096970-05
Application #
8627196
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Mcdonald, Cheryl
Project Start
2010-04-20
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$372,549
Indirect Cost
$126,789
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Otsuka, Fumiyuki; Vorpahl, Marc; Nakano, Masataka et al. (2014) Pathology of second-generation everolimus-eluting stents versus first-generation sirolimus- and paclitaxel-eluting stents in humans. Circulation 129:211-23
Habib, Anwer; Karmali, Vinit; John, Michael C et al. (2014) Everolimus-eluting stents improve vascular response in a diabetic animal model. Circ Cardiovasc Interv 7:526-32
Sakakura, Kenichi; Nakano, Masataka; Otsuka, Fumiyuki et al. (2014) Comparison of pathology of chronic total occlusion with and without coronary artery bypass graft. Eur Heart J 35:1683-93
Nakano, Masataka; Yahagi, Kazuyuki; Otsuka, Fumiyuki et al. (2014) Causes of early stent thrombosis in patients presenting with acute coronary syndrome: an ex vivo human autopsy study. J Am Coll Cardiol 63:2510-20
Habib, Anwer; Karmali, Vinit; Polavarapu, Rohini et al. (2013) Metformin impairs endothelialization after placement of newer generation drug eluting stents. Atherosclerosis 229:385-7
Otsuka, Fumiyuki; Finn, Aloke V; Virmani, Renu (2013) Do vulnerable and ruptured plaques hide in heavily calcified arteries? Atherosclerosis 229:34-7
Habib, Anwer; Karmali, Vinit; Polavarapu, Rohini et al. (2013) Metformin impairs vascular endothelial recovery after stent placement in the setting of locally eluted mammalian target of rapamycin inhibitors via S6 kinase-dependent inhibition of cell proliferation. J Am Coll Cardiol 61:971-80
Habib, Anwer; Karmali, Vinit; Polavarapu, Rohini et al. (2013) Sirolimus-FKBP12.6 impairs endothelial barrier function through protein kinase C-* activation and disruption of the p120-vascular endothelial cadherin interaction. Arterioscler Thromb Vasc Biol 33:2425-31
Saeed, Omar; Otsuka, Fumiyuki; Polavarapu, Rohini et al. (2012) Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis. Arterioscler Thromb Vasc Biol 32:299-307
Finn, Aloke V; Otsuka, Fumiyuki (2012) Neoatherosclerosis: a culprit in very late stent thrombosis. Circ Cardiovasc Interv 5:6-9

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