4.11. Tools for Studying Diabetic Vascular Complications and Information on the Safety and Effects of a Gene Therapy Approach

Public examination of a doctoral dissertation in the field of Pharmacology

Doctoral candidate: Suvi Heinonen, M.Sc. (Pharmacy), M.Sc. (Biotechnology)

Time and venue: 4.11.2011 at 12 noon, Mediteknia Auditorium, Kuopio Campus

Language of the public examination: Finnish

Language of the doctoral dissertation: English

Cardiovascular complications are the major cause of morbidity and mortality in diabetic patients. In the doctoral thesis of Suvi Heinonen, a promising new mouse model of type 2 diabetic macrovascular complications was developed and characterized. In addition, when the safety and pharmacodynamics of a cardiovascular gene therapy approach were evaluated, no adverse effects in relation to the progression of atherosclerosis were found.

The prevalence of diabetes is increasing and especially type 2 diabetes is starting to reach epidemic proportions in the Western world. Diabetes increases the risk of cardiovascular diseases and the patients suffer from both micro- and macrovascular complications. The high prevalence of concomitant cardiovascular risk factors, the predisposition to atherogenic lipid abnormalities, and other diabetes-related biochemical and metabolic perturbations, lead to accelerated atherosclerosis. To model such complex metabolic disorders in preclinical research, animal models are essential. In recent years various mouse models combining disorders of lipid and glucose metabolism have been generated and studied, and they have provided new and valuable information. However, shortcomings remain and new models are clearly needed.

New tools for studying diabetic cardiovascular complications

Lack of proper experimental models has hindered the studying of diabetic vascular complications. In the doctoral dissertation of Suvi Heinonen, a novel mouse model representing type 2 diabetes and atherosclerosis was developed. The model demonstrated typical type 2 diabetic metabolic characteristics as well as a worsening of the atherosclerotic lesion phenotype. Subsequent to extensive coronary artery disease, severe left ventricular dysfunction was also observed. The new model combines insulin resistance, hyperglycemia and hypercholesterolemia in such a way that mimics the human patients better than the previous mouse models. Therefore it offers a new tool for studying the accelerated atherosclerosis and cardiovascular complications in diabetes, as well as for the development of new therapeutic approaches.

Safety of proangiogenic gene therapy

Since type 2 diabetic patients have an increased predisposition to atherosclerosis and related cardiovascular diseases, a growing number of patients needing revascularization procedures have diverse metabolic disorders. Due to the often diffuse vascular disease and complex clinical picture of diabetic patients, the response to treatment is often not optimal or the conventional surgical procedures cannot be performed. As a new treatment modality, gene therapy applications show promise in the treatment of CVD. In clinical trials, therapeutical angiogenesis has proven to be safe and feasible. However, increased neovascularization can contribute also to pathogenic processes, such as atherosclerotic lesion growth and the development of diabetic retinopathy, and concerns about the safety of pro-angiogenic therapies have been raised based on a few animal studies. In this thesis, the safety of adenoviral gene therapy using vascular endothelial growth factors (VEGF) was evaluated in relation to atherosclerosis. No evidence of increased atherosclerosis after a transient overexpression ofVEGF-A, -B, -C and -D in a hypercholesterolemic mouse model was found. The results support the data from clinical trials, and indicate that the testing and development of VEGF gene therapy for cardiovascular diseases can proceed without unnecessary concerns about accelerated atherogenesis.

The doctoral dissertation of Suvi Heinonen, M.Sc. (Pharmacy), M.Sc. (Biotechnology), entitled ”Modeling cardiovascular complications of diabetes mellitus - Development of a new mouse model and evaluation of a gene therapy approach” will be examined at the Faculty of Health Sciences. The opponent in the public examination will be Professor Markku Savolainen of the University of Oulu, and the custos will be Professor Seppo Ylä-Herttuala of the University of Eastern Finland.

For further information, please contact: Suvi Heinonen, A.I. Virtanen Institute for Molecular Sciences, suvi.heinonen@uef.fi, p. 040 355 3685

Publishing year: 2011

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