Effect of early administration of lower dose versus high dose of fresh mitochondria on reducing monocrotaline-induced pulmonary artery hypertension in rat.

Objective: This study aim to investigate whether early mitochondrial administration would be effective and whether high-dose mitochondria (15000 μg/rat) would be more effective than low-dose mitochondria (1500 μg/rat) for attenuating the monocrotaline (MCT/65 mg/kg/rat)-induced pulmonary artery hypertension (PAH) in rat.

Method And Results: Male-adult SD rats (n = 32) were randomized categorized into groups 1 (sham-control), 2 (PAH), 3 (PAH + low-dose mitochondria), and 4 (PAH + high-dose mitochondria). Mitochondria were admitted at day 5 and rats were sacrificed at day 35 post-MCT treatment. By day 35, oxygen saturation (saO) was highest in group 1 and lowest in group 2, and significantly higher in group 3 than in group 4 (P<0.001). Conversely, right ventricular systolic blood pressure showed an opposite pattern compared with saO among all groups (P<0.001). Histological integrity of alveolar sacs exhibited a pattern identical to saO, whereas lung crowding score and number of muscularized artery displayed an opposite pattern (all P<0.001). The protein expression of indices of inflammation (MMP-9, TNF-α, NF-κB), oxidative stress (oxidized protein, NO-1, NOX-2, NOX-4), apoptosis (Bax, cleaved caspase-3 and PARP), fibrosis (p-Smad3, TGF-β), mitochondrial-damage (cytosolic cytochrome-C), and hypoxia-smooth muscle proliferative factors (HIF-α, connexin43, TRPCs) showed an opposite pattern compared, whereas anti-fibrosis (p-Smad1/5, BMP-2) and mitochondrial integrity (mitochondrial cytochrome-C) exhibited an identical pattern to saO in all groups (all P<0.001).

Conclusion: Low dose is superior to high dose of mitochondria for protecting against MCT-induced PAH. The paradoxical beneficial effect may imply therapy with 15000 μg/rat mitochondria is overdose in this situation.