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Sildenafil therapy for early origins of heart disease

Supervisor: Dino Giussani

One in three people die of heart disease. Every three minutes someone has a heart attack and 30% of these are fatal. Therefore, there is no question that heart disease is the greatest killer in the UK today, imposing a substantial burden on our nation’s health and wealth.

We now accept that our genes interact with traditional lifestyle risk factors, such as smoking, obesity and a sedentary life to trigger a risk of heart disease. It has now also become established that the gene-environment interaction early in life is just as, if not more, important in setting a risk of heart disease. The Giussani laboratory has pioneered the contribution of chronic fetal hypoxia, the most common complication of pregnancy, in programming an increased risk of heart disease in the adult offspring. Our work has shown that the mechanism linking chronic fetal hypoxia with an increased risk of cardiovascular disease later in life is the generation of oxidative stress in the fetal cardiovascular system. Consequently, maternal treatment with the antioxidant vitamin C is protective. While this work provides proof-of-principle in potential translational therapy, only very high doses of vitamin C incompatible with human treatment were effective. Therefore, there is an urgent need for alternative translational maternal antioxidant therapy.

This PhD project will test the hypothesis that the antioxidant properties of Sildenafil will prevent the programming of heart disease in an established rodent model of pregnancy complicated by developmental hypoxia.

The work will adopt an integrative approach combining in vivo cardiovascular physiology with work at the isolated organ (Langendorff, Working Heart, Myography), cellular (Stereology), mitochondrial (oxygen consumption) and molecular (Western blot, miRNA, telomere shortening) levels. These studies will take place in the fetus at the end of pregnancy and in the 4 month young adult offspring.

References

Giussani et al. PLoS One 2012; 7(2):e31017.

Richter et al. J Physiol. 2012; 590(Pt 6):1377-87.

Herrera et al. J Vasc Res. 2012; 49(1):50-8.

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