Novel gasotransmitter intervention against programmed heart disease in the next generation
Project ID: PSM00028
Supervisor: Prof. Dino Giussani
Adverse conditions during early life can programme an increased risk of heart disease in next generation. My laboratory has shown in several animal models, including sheep, rats, mice and chickens that chronic fetal hypoxia, the most common consequence of complicated pregnancy in humans, programmes cardiovascular disease in the offspring. This includes an increased risk of cardiac ischaemic-reperfusion (IR) injury (1,2). The next phase of the work is intervention. Along with nitric oxide, hydrogen sulphide (H2S) and carbon monoxide (CO) are gasotransmitters, with recently ascribed cardio-protective actions (3). However, their role as intervention against heart disease programmed developmentally has not been investigated in any species.
This project will determine in animal models the protective mechanisms of H2S or CO on the cardiovascular system of offspring exposed to control or hypoxic conditions during development. During a PhD, outcome measures will be at two stages of the life period: at the end of fetal development and in the adult offspring. In each phase, we will adopt an integrative approach combining experiments in vivo (chronic instrumentation and echocardiography), with those at the isolated organ (Langendorff preparations and in vitro wire myography), cellular, mitochondrial, molecular and epigenetic levels.
3 Key references
1. Giussani DA, Davidge ST. J Dev Orig Health Dis. 4(5):328-37, 2013 (Review).
2. Niu et al. Hypertension 72:971–978, 2018.
3. Andreadou et al. Br J Pharmacol. 172(6):1587-606, 2015.
The study has translational links. The Pregnancy Outcome Prediction Study (POPs) study included 4,512 nulliparous women with a viable singleton pregnancy attending The Rosie Hospital (Cambridge, UK) for their dating ultrasound scan between 2008 and 2012. Some of these pregnancies include those complicated by chronic fetal hypoxia and fetal growth restriction. Plans are being assessed for cardiovascular studies in children from these pregnancies, to link their prenatal experience with their current cardiovascular health.