title: Combined therapeutic benefit of mitochondria-targeted antioxidant, MitoQ10, and angiotensin receptor blocker, losartan, on cardiovascular function.
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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: aBHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow bMRC Mitochondrial Biology Unit, Cambridge, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: McLachlan
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Beattie
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: Caline H H
authors.initials: CH
authors.lastname: Koh-Tan
authors.forename: Erin
authors.initials: E
authors.lastname: Olson
authors.forename: Wendy
authors.initials: W
authors.lastname: Beattie
authors.forename: Anna F
authors.initials: AF
authors.lastname: Dominiczak
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Nicklin
authors.forename: Delyth
authors.initials: D
authors.lastname: Graham
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D000975:Antioxidants / Q000008:administration & dosage*; D049108:Cell Enlargement / Q000187:drug effects; D002460:Cell Line; D004357:Drug Synergism; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D019808:Losartan / Q000008:administration & dosage*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009943:Organophosphorus Compounds / Q000008:administration & dosage*; D051381:Rats; D011918:Rats, Inbred SHR; D014451:Ubiquinone / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D000975:Antioxidants; D009943:Organophosphorus Compounds; D014451:Ubiquinone; C429014:mitoquinone; D019808:Losartan