Christian Rask-Madsen

Personal Information
Title Assistant Professor
Expertise Cardiovascular
Institution Joslin Diabetes Center - Boston
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Data Summary
Grants/SubContracts 1
Progress Reports 1
Publications 8
Protocols 0
Committees 2

Insulin action on endothelium in angiogenesis
Patients with obesity and type 2 diabetes have increased risk for heart failure and limb amputation, in part because of impaired neovascular response in hypoxic tissue. Insulin action directly on vascular endothelium can activate proangiogenic mechanisms such as generation of nitric oxide (NO). Therefore, insulin resistance in endothelial cells could help explain compromised neovascularization in ischemic tissues in conditions with insulin resistance. Based on strong preliminary data, we hypothesize that insulin action on endothelial cells, through inhibition of the transcription factor FoxO, can regulate angiogenic or angiostatic genes and thereby promote angiogenesis in muscle. In Aim 1, we will determine the contribution to angiogenesis of insulin receptor signaling in endothelial cells. Blood flow, collateral formation, and angiogenesis will be quantitated in the ischemic hindlimb after femoral artery ligation and compared with these parameters in the contralateral leg, using mice with knockout of the insulin receptor restricted to endothelial cells or their littermate controls. In Aim 2, we will determine the relative contribution of FoxO1 or FoxO3 to insulin signaling and cell function in endothelial cell culture by adenovirus-mediated expression of FoxO constructs. We will also screen for insulin-stimulated regulation of 23 genes previously documented as being regulated by FoxO and determine which of these genes mediate proangiogenic cell function by shRNA-mediated knockdown of candidate genes using lentivirus as vectors. Relevance. This work will provide an animal model of impaired angiogenesis in conditions with insulin resistance and identify insulin-regulated genes in endothelial cells which modifies angiogenesis. Ultimately, results from this research may guide development of insulin analogs and insulin sensitizers and identify novel targets for improving heart and limb function in complications of obesity and type 2 diabetes.

Progress Reports
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Insulin action on endothelium in angiogenesis (Rask-Madsen, Christian)
11/26/2013View Progress Report Document

Annual Reports
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Year: 2016; Items: 1

Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells.
Wang X, Lockhart SM, Rathjen T, Albadawi H, Sørensen D, O'Neill BT, Dwivedi N, Preil SR, Beck HC, Dunwoodie SL, Watkins MT, Rasmussen LM, Rask-Madsen C
Diabetes, 2016

Year: 2013; Items: 2

Vascular complications of diabetes: mechanisms of injury and protective factors.
Rask-Madsen C, King GL
Cell Metabolism, 2013 (17), 20 - 33
Submitted Externally
Induction of vascular insulin resistance and endothelin-1 expression and acceleration of atherosclerosis by the overexpression of protein kinase C-ß isoform in the endothelium.
Li Q, Park K, Li C, Rask-Madsen C, Mima A, Qi W, Mizutani K, Huang P, King GL
Circulation research, 2013 (113), 418 - 427
Submitted Externally

Year: 2012; Items: 3

Glomerular VEGF resistance induced by PKCd/SHP-1 activation and contribution to diabetic nephropathy.
Mima A, Kitada M, Geraldes P, Li Q, Matsumoto M, Mizutani K, Qi W, Li C, Leitges M, Rask-Madsen C, King GL
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2012 (26), 2963 - 2974
Protective effects of GLP-1 on glomerular endothelium and its inhibition by PKCß activation in diabetes.
Mima A, Hiraoka-Yamomoto J, Li Q, Kitada M, Li C, Geraldes P, Matsumoto M, Mizutani K, Park K, Cahill C, Nishikawa S, Rask-Madsen C, King GL
Diabetes, 2012 (61), 2967 - 2979
Retinal not systemic oxidative and inflammatory stress correlated with VEGF expression in rodent models of insulin resistance and diabetes.
Mima A, Qi W, Hiraoka-Yamomoto J, Park K, Matsumoto M, Kitada M, Li Q, Mizutani K, Yu E, Shimada T, Lee J, Shoelson SE, Jobin C, Rask-Madsen C, King GL
Investigative ophthalmology & visual science, 2012 (53), 8424 - 8432

Year: 2011; Items: 2

Glomerular-specific protein kinase C-ß-induced insulin receptor substrate-1 dysfunction and insulin resistance in rat models of diabetes and obesity.
Mima A, Ohshiro Y, Kitada M, Matsumoto M, Geraldes P, Li C, Li Q, White GS, Cahill C, Rask-Madsen C, King GL
Kidney international, 2011 (79), 883 - 896
The effect of chronic heart failure and type 2 diabetes on insulin-stimulated endothelial function is similar and additive.
Falskov B, Hermann TS, Rask-Madsen C, Major-Pedersen A, Christiansen B, Raunsø J, Køber L, Torp-Pedersen C, Dominguez H
Vascular health and risk management, 2011 (7), 771 - 776
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