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.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.

Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

“…In addition, MitoQ10 was shown to mediate a direct antihypertrophic effect on rat cardiomyocytes in vitro. These results endorse MitoQ10's potential as a novel therapeutic intervention in conjunction with current antihypertensive drugs (194). MitoQ has also been shown to be beneficial in a rat model of sepsis, a pathological process characterized by a systemic dysregulated inflammatory response and oxidative stress, often leading to organ dysfunction, organ failure, and death.…”

Mitochondrial dysfunction in cardiac aging

“…MitoQ has been shown to help maintain eNOS availability and reduce hypertension. MitoQ has been given together with losartan, an angiotensin receptor blocker, that did not decrease ROS production in the mitochondria, but the combined therapy did lead to an improvement in cardiovascular function [207]. SkQ1 is another mitochondrial targeted antioxidant that has been reported to extend lifespan in male BALB/c mice and dwarf hamsters [209].…”

Treatment of Hypertension with Nutrition and Nutraceutical Supplements: Part 2

“…55 Coenzyme Q10 (ubiquinone) Coenzyme Q10 (CoQ10; ubiquinone) has consistent and significant antihypertensive effects in hypertensive subjects. [1][2][3][4][40][41][42][43][44][45][46][47][48][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73] CoQ10 increases eNOS and NO and improves endothelial function and vascular elasticity. [1][2][3][4][40][41][42][43][44][45][46][47][48]65,66 CoQ10 serum levels decrease with age, chronic disease, oxidative stress, dyslipidemia, coronary heart disease (CHD), hypertension, diabetes mellitus (DM), statin and beta-blocker use, exercise, and atherosclerosis.…”

“…[1][2][3][4]56,61,67,68,74 Combining a targeted intracellular cardiac CoQ10 (MitoQ10) and low-dose losartan provides additive therapeutic benefit, significantly attenuating development of hypertension, increasing NO levels, and reducing left ventricular hypertrophy in the spontaneously hypertensive stroke prone rat. 72 In addition, MitoQ10 mediates a direct anti-hypertrophic effect on rat cardiomyocytes in vitro.…”