Antioxidant-Conjugated Peptide Attenuated Metabolic Reprogramming in Pulmonary Hypertension
Pulmonary arterial hypertension (PAH) is a chronic cardiopulmonary disorder instigated by pulmonary vascular cell proliferation. Activation of Akt was previously reported to promote vascular remodeling. Also, the irreversible nitration of Y350 residue in Akt results in its activation. NitroAkt was i...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-01-01
|
| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/9/2/104 |
| _version_ | 1797765712077389824 |
|---|---|
| author | Mathews Valuparampil Varghese Maki Niihori Cody A Eccles Sergey Kurdyukov Joel James Olga Rafikova Ruslan Rafikov |
| author_facet | Mathews Valuparampil Varghese Maki Niihori Cody A Eccles Sergey Kurdyukov Joel James Olga Rafikova Ruslan Rafikov |
| author_sort | Mathews Valuparampil Varghese |
| collection | DOAJ |
| description | Pulmonary arterial hypertension (PAH) is a chronic cardiopulmonary disorder instigated by pulmonary vascular cell proliferation. Activation of Akt was previously reported to promote vascular remodeling. Also, the irreversible nitration of Y350 residue in Akt results in its activation. NitroAkt was increased in PAH patients and the SU5416/Hypoxia (SU/Hx) PAH model. This study investigated whether the prevention of Akt nitration in PAH by Akt targeted nitroxide-conjugated peptide (NP) could reverse vascular remodeling and metabolic reprogramming. Treatment of the SU/Hx model with NP significantly decreased nitration of Akt in lungs, attenuated right ventricle (RV) hypertrophy, and reduced RV systolic pressure. In the PAH model, Akt-nitration induces glycolysis by activation of the glucose transporter Glut4 and lactate dehydrogenase-A (LDHA). Decreased G6PD and increased GSK3β in SU/Hx additionally shunted intracellular glucose via glycolysis. The increased glycolytic rate upregulated anaplerosis due to activation of pyruvate carboxylase in a nitroAkt-dependent manner. NP treatment resolved glycolytic switch and activated collateral pentose phosphate and glycogenesis pathways. Prevention of Akt-nitration significantly controlled pyruvate in oxidative phosphorylation by decreasing lactate and increasing pyruvate dehydrogenases activities. Histopathological studies showed significantly reduced pulmonary vascular proliferation. Based on our current observation, preventing Akt-nitration by using an Akt-targeted nitroxide-conjugated peptide could be a useful treatment option for controlling vascular proliferation in PAH. |
| first_indexed | 2024-03-12T20:15:00Z |
| format | Article |
| id | doaj.art-d702ca3aac01466b8f9a01bbcbc6ae70 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-12T20:15:00Z |
| publishDate | 2020-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-d702ca3aac01466b8f9a01bbcbc6ae702023-08-02T01:26:24ZengMDPI AGAntioxidants2076-39212020-01-019210410.3390/antiox9020104antiox9020104Antioxidant-Conjugated Peptide Attenuated Metabolic Reprogramming in Pulmonary HypertensionMathews Valuparampil Varghese0Maki Niihori1Cody A Eccles2Sergey Kurdyukov3Joel James4Olga Rafikova5Ruslan Rafikov6Department of Medicine, Division of Endocrinology, University of Arizona College of Medicine, Tucson, AZ 85721, USADepartment of Medicine, Division of Endocrinology, University of Arizona College of Medicine, Tucson, AZ 85721, USADepartment of Medicine, Division of Endocrinology, University of Arizona College of Medicine, Tucson, AZ 85721, USADepartment of Medicine, Division of Endocrinology, University of Arizona College of Medicine, Tucson, AZ 85721, USADepartment of Medicine, Division of Endocrinology, University of Arizona College of Medicine, Tucson, AZ 85721, USADepartment of Medicine, Division of Endocrinology, University of Arizona College of Medicine, Tucson, AZ 85721, USADepartment of Medicine, Division of Endocrinology, University of Arizona College of Medicine, Tucson, AZ 85721, USAPulmonary arterial hypertension (PAH) is a chronic cardiopulmonary disorder instigated by pulmonary vascular cell proliferation. Activation of Akt was previously reported to promote vascular remodeling. Also, the irreversible nitration of Y350 residue in Akt results in its activation. NitroAkt was increased in PAH patients and the SU5416/Hypoxia (SU/Hx) PAH model. This study investigated whether the prevention of Akt nitration in PAH by Akt targeted nitroxide-conjugated peptide (NP) could reverse vascular remodeling and metabolic reprogramming. Treatment of the SU/Hx model with NP significantly decreased nitration of Akt in lungs, attenuated right ventricle (RV) hypertrophy, and reduced RV systolic pressure. In the PAH model, Akt-nitration induces glycolysis by activation of the glucose transporter Glut4 and lactate dehydrogenase-A (LDHA). Decreased G6PD and increased GSK3β in SU/Hx additionally shunted intracellular glucose via glycolysis. The increased glycolytic rate upregulated anaplerosis due to activation of pyruvate carboxylase in a nitroAkt-dependent manner. NP treatment resolved glycolytic switch and activated collateral pentose phosphate and glycogenesis pathways. Prevention of Akt-nitration significantly controlled pyruvate in oxidative phosphorylation by decreasing lactate and increasing pyruvate dehydrogenases activities. Histopathological studies showed significantly reduced pulmonary vascular proliferation. Based on our current observation, preventing Akt-nitration by using an Akt-targeted nitroxide-conjugated peptide could be a useful treatment option for controlling vascular proliferation in PAH.https://www.mdpi.com/2076-3921/9/2/104pulmonary arterial hypertensionmetabolismwarburg effectanaplerosisnitroxide-conjugated peptideakt |
| spellingShingle | Mathews Valuparampil Varghese Maki Niihori Cody A Eccles Sergey Kurdyukov Joel James Olga Rafikova Ruslan Rafikov Antioxidant-Conjugated Peptide Attenuated Metabolic Reprogramming in Pulmonary Hypertension Antioxidants pulmonary arterial hypertension metabolism warburg effect anaplerosis nitroxide-conjugated peptide akt |
| title | Antioxidant-Conjugated Peptide Attenuated Metabolic Reprogramming in Pulmonary Hypertension |
| title_full | Antioxidant-Conjugated Peptide Attenuated Metabolic Reprogramming in Pulmonary Hypertension |
| title_fullStr | Antioxidant-Conjugated Peptide Attenuated Metabolic Reprogramming in Pulmonary Hypertension |
| title_full_unstemmed | Antioxidant-Conjugated Peptide Attenuated Metabolic Reprogramming in Pulmonary Hypertension |
| title_short | Antioxidant-Conjugated Peptide Attenuated Metabolic Reprogramming in Pulmonary Hypertension |
| title_sort | antioxidant conjugated peptide attenuated metabolic reprogramming in pulmonary hypertension |
| topic | pulmonary arterial hypertension metabolism warburg effect anaplerosis nitroxide-conjugated peptide akt |
| url | https://www.mdpi.com/2076-3921/9/2/104 |
| work_keys_str_mv | AT mathewsvaluparampilvarghese antioxidantconjugatedpeptideattenuatedmetabolicreprogramminginpulmonaryhypertension AT makiniihori antioxidantconjugatedpeptideattenuatedmetabolicreprogramminginpulmonaryhypertension AT codyaeccles antioxidantconjugatedpeptideattenuatedmetabolicreprogramminginpulmonaryhypertension AT sergeykurdyukov antioxidantconjugatedpeptideattenuatedmetabolicreprogramminginpulmonaryhypertension AT joeljames antioxidantconjugatedpeptideattenuatedmetabolicreprogramminginpulmonaryhypertension AT olgarafikova antioxidantconjugatedpeptideattenuatedmetabolicreprogramminginpulmonaryhypertension AT ruslanrafikov antioxidantconjugatedpeptideattenuatedmetabolicreprogramminginpulmonaryhypertension |