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

TitleCombined therapeutic benefit of mitochondria-targeted antioxidant, MitoQ10, and angiotensin receptor blocker, losartan, on cardiovascular function.
Publication TypeJournal Article
Year of Publication2014
AuthorsMcLachlan, J, Beattie, E, Murphy, MP, Koh-Tan, CHH, Olson, E, Beattie, W, Dominiczak, AF, Nicklin, SA, Graham, D
JournalJ Hypertens
Volume32
Issue3
Pagination555-64
Date Published2014 Mar
ISSN1473-5598
KeywordsAngiotensin II Type 1 Receptor Blockers, Animals, Antihypertensive Agents, Antioxidants, Cell Enlargement, Cell Line, Drug Synergism, Hypertension, Hypertrophy, Left Ventricular, Losartan, Male, Myocytes, Cardiac, Organophosphorus Compounds, Rats, Rats, Inbred SHR, Ubiquinone
Abstract

OBJECTIVE: 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, MitoQ10, with the low-dose angiotensin receptor blocker (ARB), losartan, on attenuation of hypertension and left ventricular hypertrophy. In parallel, we investigated the impact of MitoQ10 on cardiac hypertrophy in a neonatal cardiomyocyte cell line.METHODS AND RESULTS: Eight-week-old male stroke-prone spontaneously hypertensive rats (SHRSPs, n=8-11) were treated with low-dose losartan (2.5 mg/kg per day); MitoQ10 (500 μmol/l); a combination of MitoQ10 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, MitoQ10 significantly inhibited angiotensin II mediated hypertrophy in a dose-dependent manner (500  nmol/l MitoQ10 153.7 ± 3.1 microns vs. angiotensin II 200.1 ± 3.6 microns, P<0.001).CONCLUSION: Combining MitoQ10 and low-dose losartan provides additive therapeutic benefit, significantly attenuating development of hypertension and reducing left ventricular hypertrophy. In addition, MitoQ10 mediates a direct antihypertrophic effect on rat cardiomyocytes in vitro. MitoQ10 has potential as a novel therapeutic intervention in conjunction with current antihypertensive drugs.

DOI10.1097/HJH.0000000000000054
Alternate JournalJ. Hypertens.
Citation Key10.1097/HJH.0000000000000054
PubMed ID24309493
PubMed Central IDPMC3914904
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom
PG/11/82/29136 / / British Heart Foundation / United Kingdom
CH98001 / / British Heart Foundation / United Kingdom