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

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, MitoQ(10), 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(10) 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); MitoQ(10) (500 mu mol/l); a combination of MitoQ(10) 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 MitoQ(10) 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(10) significantly inhibited angiotensin II mediated hypertrophy in a dose-dependent manner (500 nmol/l MitoQ(10) 153.7 +/- 3.1 microns vs. angiotensin II 200.1 +/- 3.6 microns, P<0.001). Conclusion: Combining MitoQ(10) and low-dose losartan provides additive therapeutic benefit, significantly attenuating development of hypertension and reducing left ventricular hypertrophy. In addition, MitoQ(10) mediates a direct antihypertrophic effect on rat cardiomyocytes in vitro. MitoQ(10) has potential as a novel therapeutic intervention in conjunction with current antihypertensive drugs.