BACKGROUND: The role of tumor necrosis factor-α (TNF-α), Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, and mitochondrial Permeability Transition Pore in atorvastatin-induced cardioprotection were examined in human myocardium, in vitro. METHODS: Isometric force of contraction of human right atrial trabeculae was recorded during 30-min hypoxia and 60-min reoxygenation (control) and in the presence of atorvastatin (0.1 µM, 1 µM, 10 µM). In early reoxygenation, the TNF-α inhibitor, AG490 (inhibitor of JAK/STAT), or atractyloside (mitochondrial Permeability Transition Pore opener), were administered. Cyclosporine A (inhibitor of mitochondrial Permeability Transition Pore opening) was administered during the first minute of reoxygenation alone or in presence of atorvastatin and TNF-α inhibitor or AG490. The force of contraction (percentage of baseline) at the end of reoxygenation period was compared (mean ± SD; n = 6 in each group). Protein expression of JAK/STAT pathway was measured using Western immunoblotting. RESULTS: Atorvastatin 0.1 µM (70 ± 9%), 1 µM (85 ± 5%), 10 µM (89 ± 5%), and Cyclosporine A (87 ± 10%) improved the recovery of force of contraction at the end of reoxygenation, as compared with control (50 ± 3%). Atorvastatin 1 µM (4.64 ± 2.90 ng · ml(-1) · g(-1) of tissue) decreased the release of troponin Ic after hypoxia-reoxygenation (control: 26.34 ± 19.30 ng · ml(-1) · g(-1); P < 0.001). The enhanced recovery of force of contraction after atorvastatin administration was abolished by TNF-α inhibitor (53 ± 8%), AG490 (56 ± 7%), atractyloside (48 ± 8%). Cyclosporine A restored the atorvastatin-induced cardioprotection abolished by TNF-α inhibitor (87 ± 6%) and AG490 (83 ± 9%). Atorvastatin significantly increased the phosphorylation of JAK-2 and STAT-3, TNF-α inhibitor abolished the enhanced phosphorylation of JAK-2 and STAT-3 by atorvastatin. CONCLUSIONS: Atorvastatin-induced cardioprotection involved the inhibition of the mitochondrial Permeability Transition Pore opening via the activation of TNF-α and the JAK/STAT pathway in early reoxygenation.
BACKGROUND: The role of tumor necrosis factor-α (TNF-α), Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, and mitochondrial Permeability Transition Pore in atorvastatin-induced cardioprotection were examined in human myocardium, in vitro. METHODS: Isometric force of contraction of human right atrial trabeculae was recorded during 30-min hypoxia and 60-min reoxygenation (control) and in the presence of atorvastatin (0.1 µM, 1 µM, 10 µM). In early reoxygenation, the TNF-α inhibitor, AG490 (inhibitor of JAK/STAT), or atractyloside (mitochondrial Permeability Transition Pore opener), were administered. Cyclosporine A (inhibitor of mitochondrial Permeability Transition Pore opening) was administered during the first minute of reoxygenation alone or in presence of atorvastatin and TNF-α inhibitor or AG490. The force of contraction (percentage of baseline) at the end of reoxygenation period was compared (mean ± SD; n = 6 in each group). Protein expression of JAK/STAT pathway was measured using Western immunoblotting. RESULTS:Atorvastatin 0.1 µM (70 ± 9%), 1 µM (85 ± 5%), 10 µM (89 ± 5%), and Cyclosporine A (87 ± 10%) improved the recovery of force of contraction at the end of reoxygenation, as compared with control (50 ± 3%). Atorvastatin 1 µM (4.64 ± 2.90 ng · ml(-1) · g(-1) of tissue) decreased the release of troponin Ic after hypoxia-reoxygenation (control: 26.34 ± 19.30 ng · ml(-1) · g(-1); P < 0.001). The enhanced recovery of force of contraction after atorvastatin administration was abolished by TNF-α inhibitor (53 ± 8%), AG490 (56 ± 7%), atractyloside (48 ± 8%). Cyclosporine A restored the atorvastatin-induced cardioprotection abolished by TNF-α inhibitor (87 ± 6%) and AG490 (83 ± 9%). Atorvastatin significantly increased the phosphorylation of JAK-2 and STAT-3, TNF-α inhibitor abolished the enhanced phosphorylation of JAK-2 and STAT-3 by atorvastatin. CONCLUSIONS:Atorvastatin-induced cardioprotection involved the inhibition of the mitochondrial Permeability Transition Pore opening via the activation of TNF-α and the JAK/STAT pathway in early reoxygenation.