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Effects of combination treatment with a novel mitochondrial antioxidant, MitoQ10 and low-dose Losartan, in the stroke-prone spontaneously hypertensive rat.

McLachlan, Jennifer C. (2012) Effects of combination treatment with a novel mitochondrial antioxidant, MitoQ10 and low-dose Losartan, in the stroke-prone spontaneously hypertensive rat. PhD thesis, University of Glasgow.

Due to Embargo and/or Third Party Copyright restrictions, this thesis is not available in this service.

Abstract

Mitochondria-derived reactive oxygen species (ROS) play an important role in the development of cardiovascular disease. Conventional antioxidants cannot impact mitochondria-derived ROS due to their limited accumulation within mitochondria, highlighting the need for novel targeted therapies. This has led to the development of antioxidants, such as MitoQ10, which can specifically accumulate within mitochondria. We have previously confirmed the significance of mitochondria-derived ROS in the pathology of the stroke-prone spontaneously hypertensive rat (SHRSP), an excellent model of human essential hypertension. It has previously been shown that MitoQ10 antioxidant therapy has important antihypertensive action in young SHRSP, emphasising a key role for mitochondrial oxidative stress in the development of hypertension. It was concluded that the small reduction in blood pressure controlled by the novel mitochondrial antioxidant could provide added benefit to current antihypertensive therapies, none of which directly target mitochondria. Resistant hypertension remains a common problem with an estimated prevalence of 20-30 %, despite a three drug regimen. This suggests the existence of blood pressure elevating mechanisms which are not fully addressed by current antihypertensive therapies. MitoQ10 could represent an important novel therapeutic agent for resistant hypertension and end-organ damage if combined with established antihypertensive drugs. The aims of this study were to investigate the potential complementary effects of a combined therapeutic strategy on the development of hypertension and cardiac hypertrophy in SHRSP using the mitochondria-targeted antioxidant MitoQ10 and a low-dose angiotensin receptor blocker (ARB), Losartan. In parallel, the direct contribution of mitochondrial oxidative damage to cardiomyocyte hypertrophy was investigated in vitro using a cardiomyocyte cell line. This study demonstrates that MitoQ10 provides complementary, additive therapeutic benefit to established antihypertensive agents. Our data suggests that MitoQ10 targets hypertensive, hypertrophic and fibrotic mechanisms involving mitochondrial oxidative damage that are not fully addressed by current antihypertensive drugs. Therefore, oral administration of the combination therapy provided additive therapeutic benefit, significantly attenuating development of hypertension and reducing cardiac and left ventricular hypertrophy. Furthermore, the in vitro results demonstrate that MitoQ10 has a direct anti-hypertrophic effect in cardiomyocytes indicating its in vivo action may be partly independent of blood pressure lowering. MitoQ10 has potential as a novel therapeutic intervention in conjunction with current antihypertensive drugs to provide additive effects against the morbidity and mortality associated with resistant hypertension and related organ damage in humans.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Due to copyright restrictions the full text of this thesis cannot be made available online. Access to the printed version is available once any embargo periods have expired.
Keywords: mitochondria, reactive oxygen species, cardiovascular disease, antioxidant, hypertension, hypertrophy, stroke-prone spontaneously hypertensive rat
Subjects: R Medicine > R Medicine (General)
Q Science > Q Science (General)
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Supervisor's Name: Graham, Dr. Delyth
Date of Award: 2012
Embargo Date: 26 January 2015
Depositing User: Miss Jennifer C McLachlan
Unique ID: glathesis:2012-3151
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 31 Jan 2012
Last Modified: 10 Dec 2012 14:04
URI: http://theses.gla.ac.uk/id/eprint/3151

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