Combined therapeutic benefit of mitochondria-targeted antioxidant, MitoQ10, and angiotensin receptor blocker, losartan, on cardiovascular function

McLachlan, J., Beattie, E., Murphy, M. P., Koh-Tan, C. H.H., Olson, E., Beattie, W., Dominiczak, A. F. , Nicklin, S. A. and Graham, D. (2014) Combined therapeutic benefit of mitochondria-targeted antioxidant, MitoQ10, and angiotensin receptor blocker, losartan, on cardiovascular function. Journal of Hypertension, 32(3), pp. 555-564. (doi:10.1097/HJH.0000000000000054)

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Publisher's URL: http://dx.doi.org/10.1097/HJH.0000000000000054

Abstract

<b>Objective:</b><p></p> Mitochondria-derived reactive oxygen species (ROS) play important roles in the development of cardiovascular disease highlighting the need for novel targeted therapies. This study assessed the potential therapeutic benefit of combining the mitochondria-specific antioxidant, MitoQ<sub>10</sub>, with the low-dose angiotensin receptor blocker (ARB), losartan, on attenuation of hypertension and left ventricular hypertrophy. In parallel, we investigated the impact of MitoQ<sub>10</sub> on cardiac hypertrophy in a neonatal cardiomyocyte cell line.<p></p> <b>Methods and results:</b><p></p> Eight-week-old male stroke-prone spontaneously hypertensive rats (SHRSPs, <i>n</i> = 8–11) were treated with low-dose losartan (2.5 mg/kg per day); MitoQ<sub>10</sub> (500 μmol/l); a combination of MitoQ<sub>10</sub> and losartan (M + L); or vehicle for 8 weeks. Systolic pressure and pulse pressure were significantly lower in M + L rats (167.1 ± 2.9 mmHg; 50.2 ± 2.05 mmHg) than in untreated SHRSP (206.6 ± 9 mmHg, P < 0.001; 63.7 ± 2.7 mmHg, P = 0.001) and demonstrated greater improvement than MitoQ10 or low-dose losartan alone, as measured by radiotelemetry. Left ventricular mass index was significantly reduced from 22.8 ± 0.74 to 20.1 ± 0.61 mg/mm in the combination group (P < 0.05). Picrosirius red staining showed significantly reduced cardiac fibrosis in M + L rats (0.82 ± 0.22 A.U.) compared with control (5.94 ± 1.35 A.U., P < 0.01). In H9c2 neonatal rat cardiomyocytes, MitoQ<sub>10</sub> significantly inhibited angiotensin II mediated hypertrophy in a dose-dependent manner (500 nmol/l MitoQ<sub>10</sub> 153.7 ± 3.1 microns vs. angiotensin II 200.1 ± 3.6 microns, P <0.001).<p></p> <b>Conclusion:</b><p></p> Combining MitoQ<sub>10</sub> and low-dose losartan provides additive therapeutic benefit, significantly attenuating development of hypertension and reducing left ventricular hypertrophy. In addition, MitoQ<sub>10</sub> mediates a direct antihypertrophic effect on rat cardiomyocytes <i>in vitro</i>. MitoQ<sub>10</sub> has potential as a novel therapeutic intervention in conjunction with current antihypertensive drugs.<p></p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nicklin, Professor Stuart and Graham, Dr Delyth and Dominiczak, Professor Anna and Beattie, Mrs Elisabeth and Beattie, Mrs Wendy
Authors: McLachlan, J., Beattie, E., Murphy, M. P., Koh-Tan, C. H.H., Olson, E., Beattie, W., Dominiczak, A. F., Nicklin, S. A., and Graham, D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of Hypertension
Publisher:Lippincott Williams & Wilkins
ISSN:0263-6352
ISSN (Online):1473-5598
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in Journal of Hypertension 32(3):555-564
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
455471Mechanism of cardiovascular disease prevention by MitoQ, a novel mitochondria-targeted antioxidantAnna DominiczakBritish Heart Foundation (BHF)FS/07/029RI CARDIOVASCULAR & MEDICAL SCIENCES
584561The mitochondrial-targeted antioxidant, MitoQ10: a novel therapeutic agent for cardiovascular disease.Delyth GrahamBritish Heart Foundation (BHF)PG/11/82/29136RI CARDIOVASCULAR & MEDICAL SCIENCES
464051Genomics and proteomics of hypertension and its vascular complications: the pathwayomic strategies.Anna DominiczakBritish Heart Foundation (BHF)RG/07/005/23633RI CARDIOVASCULAR & MEDICAL SCIENCES