부산대학교 도서관

Post-menopausal women have an enhanced risk of developing cardiovascular disease and disturbances of cardiac rhythm, that have been attributed to declining oestrogen levels during menopause. This highlights the requirement to understand the effect of declining oestrogen levels and oestrogen signalling on cardiac structural remodelling and electrophysiology. This thesis addressed the hypotheses that cardiomyocytes undergo remodellingin response to long-term oestrogen withdrawal following ovariectomy (OVx) that may contribute to altered excitation-contraction (EC) coupling in the heart that such changes may involve the G protein-coupled oestrogen receptor 1 (GPER). OVx or sham surgeries were performed in female guinea pigs. Left ventricular cardiomyocytes were isolatedfor experimental use. Cellular t-tubule network and structural integrity were assessed using membrane staining and scanning ion conductance microscopy. Electrophysiological, fluorescence imaging and molecular biology techniques were utilised to investigate the effect of oestrogen withdrawal and GPER signalling on EC coupling. GPER was targeted with the agonist, G-1 or antagonist G36. Following OVx, t-tubule density decreased by 13% and these cells presented with larger Ca2+transients, prolonged action potential duration(APD) as well as increased spontaneous Ca2+activity and abnormal depolarisations that led to the formation of a pro-arrhythmic substrate. GPER localised to the t-tubules and its expressionincreased by32% in OVx. GPER activation reduced Ca2+transient amplitude (by 40%), shortened the APD (by 22%) and near abolished the formation of early after-depolarisations (by >96%). GPER appears to mediate these cardioprotective changes via the downstream effectors cAMP and eNOS, which were both upregulated in the presence of G-1. In an animal species with comparable steroidogenesis and cardiac physiology to humans, it is shown that adverse remodelling and Ca2+signalling occurred in cardiomyocytes following oestrogen deficiency. GPER activation induced negative inotropic responses and anti-arrhythmogenic behaviours, indicating the potential benefits of targeting oestrogenic signalling.