Cardiovascular disease is the leading cause of death globally. Chronic hypertension can lead to a gradual deterioration in the structure and performance of the cardiovascular system in a process described as cardiovascular remodelling. The ultimate response to this remodelling is heart failure. While cardiovascular remodelling is characterised by features such as cardiac and vascular hypertrophy, endothelial dysfunction and fibrosis; mechanisms leading to such pathologies are still unclear. However, oxidative stress, the damage caused by increased production of reactive oxygen species such as free radicals, or their reduced removal by anti-oxidants, appears to have a significant role. The major aim of this thesis is to investigate the involvement of reactive oxygen species in cardiovascular remodelling and to further investigate the potentials of three anti-oxidant approaches (a combination of alpha-lipoic acid and vitamin E, apocynin and a red-wine component, resveratrol) in preventing or reversing cardiovascular remodelling. These studies were conducted in two well-established rat models of cardiovascular remodelling including the deoxycorticosterone acetate (DOCA)-salt hypertensive rat and the ageing spontaneously hypertensive rat (SHR). Additionally, this thesis also characterises the effects of ovariectomy on the blood pressure and survival rate of female SHR. The cardiovascular structure and function in the animals have been defined using in vivo echocardiography, ex vivo isolated Langendorff heart perfusion, isolated thoracic aortic rings, histological analysis of the myocardial extracellular matrix and inflammation along with terminal organ weight measurements. Reactive oxygen species were assessed through the measurement of plasma malondialdehyde (MDA) while the anti-oxidant capacities have been assessed through measurements of plasma total anti-oxidant status (TAS) and plasma glutathione peroxidase (GPx) activity. DOCA-salt treated rats exhibited hypertension, oxidative stress and cardiovascular remodelling, evidenced by their increased left ventricular weights, excess collagen deposition in the heart and increased values for diastolic stiffness, increased plasma MDA concentrations along with impaired contraction and relaxation of the vessels. Treatment with a combination of alpha-lipoic acid and vitamin E or apocynin significantly inhibited the increases in blood pressure, left ventricular weights, cardiac stiffness, interstitial collagen deposition along with improvements in the vascular responses. The treatment of ageing male SHRs with resveratrol, although without any decrease in blood pressure, was shown to reduce left ventricular hypertrophy, fibrosis, diastolic stiffness and improve functional performance of the heart. The level of oxidative stress was also lowered in the male SHRs treated with resveratrol as evidenced by decreased plasma MDA and increased TAS. Female SHRs had a higher blood pressure and diastolic stiffness compared to their age-matched WKYs. Similar to male SHRs, treatment with resveratrol did not affect blood pressure, but attenuated the increased diastolic stiffness, in female SHRs. Furthermore, the ovariectomised SHRs were proven to be extremely hypertensive and had a significantly poorer survival rate. Overall, these studies demonstrated great potential for the alpha-lipoic acid and vitamin E combination and apocynin in the treatment of cardiovascular remodelling. However, further clinical and experimental research is essential to confirm the complete cardiovascular health benefits of resveratrol or red wine intake.
| Identifer | oai:union.ndltd.org:ADTP/254182 |
| Creators | Prasad Chunduri |
| Source Sets | Australiasian Digital Theses Program |
| Detected Language | English |
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