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“Hypertrophic” Signal Transduction Pathways in the Decompensated Right Ventricle Muscle in an Animal Model of Pulmonary Hypertension
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A6132 - “Hypertrophic” Signal Transduction Pathways in the Decompensated Right Ventricle Muscle in an Animal Model of Pulmonary Hypertension
Author Block: R. Rogers1, M. Fournier1, R. C. Middleton1, E. Marban1, M. I. Lewis2; 1Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 2Heart Institute, Pulmonary Division, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Introduction: We have previously reported that several signal transduction pathways important in muscle protein synthesis and hypertrophy were upregulated in the right ventricle (RV) of the monocrotaline (MCT) rat model of pulmonary hypertension (PH) during adaptive RV hypertrophy. These included the PI3K/Akt/mTOR, GSK3 and ERK pathways (AJRCCM 2013;187: A3983).
Aims: The aim of this study was to evaluate the same signaling pathways in MCT-PH rats complicated by significant RV dysfunction and right heart failure (RHF).
Methods: Male rats received 60mg/kg of MCT by SC injection. The presence of RHF was determined by reduced TAPSE and CO determined by transthoracic Echo. Signaling protein expression in the RV muscle was measured using SDS-PAGE and Western blotting, and IGF-1 by high sensitivity ELISA.
Results: The rats were examined > 42 days after MCT administration. TAPSE and CO were markedly reduced compared with control (CTL) and PH rats at day 28 post MCT. (TAPSE: CTL: 3.1mm, MCT28: 2.3mm; RHF: 1.3mm. CO: CTL: 108ml/min; MCT28: 80ml/min; RHF: 69 ml/min). Western blot analysis revealed that mTORC1 and its downstream effector p-70S6K were significantly activated in the RV muscle of these rats. Increased p-mTOR +/- p-70S6K presumably contributed to the decreased LC3-I/II ratio, a marker of autophagy inhibition. Upstream analysis confirmed that mTORC1 was not activated via PI3K/Akt signaling as both IGF-1 protein levels and phosphorylated Akt were significantly decreased relative to CTL RVs. Both GSK3-α/β and ERK1/2 signaling were preserved during decompensation. We therefore probed for p27 which has been recently implicated in regulating mTOR activity to inhibit autophagy and promote heart failure (Su et al. CDD 2015). We confirmed that p27, a cyclin-dependent kinase (CDK) inhibitor is significantly downregulated in MCT-induced RHF.
Conclusions: These data suggest that the failing RV muscle in MCT-PH shows evidence of disrupted autophagy, in which downregulation of p27 releases its inhibitory effects on CDK to activate mTOR and inhibit autophagy and thus normal cardiomyocyte autophagic homeostasis. Upregulation of mTORC1 signaling is an Akt-independent signal transduction event. We speculate that autophagy inhibition in conjunction with other maladaptive processes reported in the decompensated RV muscle with PH, contributes to the genesis of overt RHF.
Author Block: R. Rogers1, M. Fournier1, R. C. Middleton1, E. Marban1, M. I. Lewis2; 1Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 2Heart Institute, Pulmonary Division, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Introduction: We have previously reported that several signal transduction pathways important in muscle protein synthesis and hypertrophy were upregulated in the right ventricle (RV) of the monocrotaline (MCT) rat model of pulmonary hypertension (PH) during adaptive RV hypertrophy. These included the PI3K/Akt/mTOR, GSK3 and ERK pathways (AJRCCM 2013;187: A3983).
Aims: The aim of this study was to evaluate the same signaling pathways in MCT-PH rats complicated by significant RV dysfunction and right heart failure (RHF).
Methods: Male rats received 60mg/kg of MCT by SC injection. The presence of RHF was determined by reduced TAPSE and CO determined by transthoracic Echo. Signaling protein expression in the RV muscle was measured using SDS-PAGE and Western blotting, and IGF-1 by high sensitivity ELISA.
Results: The rats were examined > 42 days after MCT administration. TAPSE and CO were markedly reduced compared with control (CTL) and PH rats at day 28 post MCT. (TAPSE: CTL: 3.1mm, MCT28: 2.3mm; RHF: 1.3mm. CO: CTL: 108ml/min; MCT28: 80ml/min; RHF: 69 ml/min). Western blot analysis revealed that mTORC1 and its downstream effector p-70S6K were significantly activated in the RV muscle of these rats. Increased p-mTOR +/- p-70S6K presumably contributed to the decreased LC3-I/II ratio, a marker of autophagy inhibition. Upstream analysis confirmed that mTORC1 was not activated via PI3K/Akt signaling as both IGF-1 protein levels and phosphorylated Akt were significantly decreased relative to CTL RVs. Both GSK3-α/β and ERK1/2 signaling were preserved during decompensation. We therefore probed for p27 which has been recently implicated in regulating mTOR activity to inhibit autophagy and promote heart failure (Su et al. CDD 2015). We confirmed that p27, a cyclin-dependent kinase (CDK) inhibitor is significantly downregulated in MCT-induced RHF.
Conclusions: These data suggest that the failing RV muscle in MCT-PH shows evidence of disrupted autophagy, in which downregulation of p27 releases its inhibitory effects on CDK to activate mTOR and inhibit autophagy and thus normal cardiomyocyte autophagic homeostasis. Upregulation of mTORC1 signaling is an Akt-independent signal transduction event. We speculate that autophagy inhibition in conjunction with other maladaptive processes reported in the decompensated RV muscle with PH, contributes to the genesis of overt RHF.
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