Chronic inhibition of mitochondrial complex III with Antimycin A induced sustained increases in right ventricle systolic pressure, perivascular edema, and a metabolic shift toward glycolysis in female rats.
Does chronic inhibition of mitochondrial complex III with Antimycin A induce pulmonary hypertension and metabolic reprogramming in a rat model?
Chronic mitochondrial complex III inhibition induces pulmonary vasoconstriction, perivascular edema, and a glycolytic shift in rats, mimicking PAH pathology, with nitrosative stress correlating with disease severity in human females.
valor p: p=<0.05
BACKGROUND: Pulmonary arterial hypertension (PAH) is a fatal disease; however, the mechanisms directly involved in triggering and the progression of PAH are not clear. Based on previous studies that demonstrated a possible role of mitochondrial dysfunction in the pathogenesis of PAH, we investigated the effects of chronic inhibition of mitochondrial function in vivo in healthy rodents. METHODS: Right ventricle systolic pressure (RVSP) was measured in female rats at baseline and up to 24 days after inhibition of mitochondrial respiratory Complex III, induced by Antimycin A (AA, 0.35 mg/kg, given three times starting at baseline and then days 3 and 6 as a bolus injection into the right atrial chamber). RESULTS: Rodents exposed to AA demonstrated sustained increases in RVSP from days 6 through 24. AA-exposed rodents also possessed a progressive increase in RV end-diastolic pressure but not RV hypertrophy, which may be attributed to either early stages of PAH development or to reduced RV contractility due to inhibition of myocardial respiration. Protein nitration levels in plasma were positively correlated with PAH development in AA-treated rats. This finding was strongly supported by results obtained from PAH humans where plasma protein nitration levels were correlated with markers of PAH severity in female but not male PAH patients. Based on previously reported associations between increased nitric oxide production levels with female gender, we speculate that in females with PAH mitochondrial dysfunction may represent a more deleterious form, in part, due to an increased nitrosative stress development. Indeed, the histological analysis of AA treated rats revealed a strong perivascular edema, a marker of pulmonary endothelial damage. Finally, AA treatment was accompanied by a severe metabolic shift toward glycolysis, a hallmark of PAH pathology. CONCLUSIONS: Chronic mitochondrial dysfunction induces the combination of vascular damage and metabolic reprogramming that may be responsible for PAH development. This mechanism may be especially important in females, perhaps due to an increased NO production and nitrosative stress development.
Rafikova et al. (Mon,) conducted a other in Pulmonary arterial hypertension. Antimycin A vs. Vehicle was evaluated on Right ventricle systolic pressure (RVSP) (p=<0.05). Chronic inhibition of mitochondrial complex III with Antimycin A induced sustained increases in right ventricle systolic pressure, perivascular edema, and a metabolic shift toward glycolysis in female rats.