Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability
Abstract Background The mechanisms involved in pulmonary hypertension (PH) development in patients and pre-clinical models are poorly understood. PH has a well-established sex dimorphism in patients with increased frequency of PH in females, and more severe disease with poor survival prognosis in ma...
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| Format: | Article |
| Language: | English |
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BMC
2020-03-01
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| Series: | Biology of Sex Differences |
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| Online Access: | http://link.springer.com/article/10.1186/s13293-020-00289-5 |
| _version_ | 1818033497551405056 |
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| author | Olga Rafikova Joel James Cody A. Eccles Sergey Kurdyukov Maki Niihori Mathews Valuparampil Varghese Ruslan Rafikov |
| author_facet | Olga Rafikova Joel James Cody A. Eccles Sergey Kurdyukov Maki Niihori Mathews Valuparampil Varghese Ruslan Rafikov |
| author_sort | Olga Rafikova |
| collection | DOAJ |
| description | Abstract Background The mechanisms involved in pulmonary hypertension (PH) development in patients and pre-clinical models are poorly understood. PH has a well-established sex dimorphism in patients with increased frequency of PH in females, and more severe disease with poor survival prognosis in males. Previously, we found that heme signaling plays an essential role in the development phase of the Sugen/Hypoxia (SU/Hx) model. This study is focused on the elucidation of sex differences in mechanisms of PH development related to heme action at the early stage of the monocrotaline (MCT) PH model. Methods Rats received MCT injection (60 mg/kg, i.p.) and followed for 14 days to investigate early disease changes. Hemodynamic parameters were recorded at the end of the study; plasma, lung homogenates, and nuclear fractions were used for the evaluation of protein levels. Results Our data indicate that on day 14, rats did not show any significant increase in the Fulton index due to the early disease phase. However, the right ventricular systolic pressure was significantly increased in male rats, while female rats showed only a trend. Interestingly, only males demonstrated an increased lung-to-bodyweight ratio that indicated lung edema. Indeed, lung histology confirmed severe perivascular edema in males. Previously, we have reported that the increased perivascular edema in SU/Hx model correlated with intravascular hemolysis and activated heme signaling. Here, we found that elevated free hemoglobin levels and perivascular edema were increased, specifically in males showing more rapid progress of PH. A high level of heme carrier protein 1 (HCP-1), which is involved in heme uptake from the bloodstream into the cells, was also found elevated in the lungs of males. The upregulation of heme oxygenase in males indicated increased intracellular heme catabolism. Increased heme signaling resulted in the activation of heme-mediated barrier-disruptive mechanisms. Thus, hemolysis in males can be responsible for increased permeability of the lungs and early disease development. Conclusions Our study indicates the importance of barrier-disruptive mechanisms as an earlier event in the induction of pulmonary hypertension. Importantly, males are more susceptible to hemolysis and develop PH earlier than females. |
| first_indexed | 2024-12-10T06:24:12Z |
| format | Article |
| id | doaj.art-291f43c415554f9aabf17c80db58e337 |
| institution | Directory Open Access Journal |
| issn | 2042-6410 |
| language | English |
| last_indexed | 2024-12-10T06:24:12Z |
| publishDate | 2020-03-01 |
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| series | Biology of Sex Differences |
| spelling | doaj.art-291f43c415554f9aabf17c80db58e3372022-12-22T01:59:16ZengBMCBiology of Sex Differences2042-64102020-03-011111910.1186/s13293-020-00289-5Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeabilityOlga Rafikova0Joel James1Cody A. Eccles2Sergey Kurdyukov3Maki Niihori4Mathews Valuparampil Varghese5Ruslan Rafikov6Division of Endocrinology, Department of Medicine, University of ArizonaDivision of Endocrinology, Department of Medicine, University of ArizonaDivision of Endocrinology, Department of Medicine, University of ArizonaDivision of Endocrinology, Department of Medicine, University of ArizonaDivision of Endocrinology, Department of Medicine, University of ArizonaDivision of Endocrinology, Department of Medicine, University of ArizonaDivision of Endocrinology, Department of Medicine, University of ArizonaAbstract Background The mechanisms involved in pulmonary hypertension (PH) development in patients and pre-clinical models are poorly understood. PH has a well-established sex dimorphism in patients with increased frequency of PH in females, and more severe disease with poor survival prognosis in males. Previously, we found that heme signaling plays an essential role in the development phase of the Sugen/Hypoxia (SU/Hx) model. This study is focused on the elucidation of sex differences in mechanisms of PH development related to heme action at the early stage of the monocrotaline (MCT) PH model. Methods Rats received MCT injection (60 mg/kg, i.p.) and followed for 14 days to investigate early disease changes. Hemodynamic parameters were recorded at the end of the study; plasma, lung homogenates, and nuclear fractions were used for the evaluation of protein levels. Results Our data indicate that on day 14, rats did not show any significant increase in the Fulton index due to the early disease phase. However, the right ventricular systolic pressure was significantly increased in male rats, while female rats showed only a trend. Interestingly, only males demonstrated an increased lung-to-bodyweight ratio that indicated lung edema. Indeed, lung histology confirmed severe perivascular edema in males. Previously, we have reported that the increased perivascular edema in SU/Hx model correlated with intravascular hemolysis and activated heme signaling. Here, we found that elevated free hemoglobin levels and perivascular edema were increased, specifically in males showing more rapid progress of PH. A high level of heme carrier protein 1 (HCP-1), which is involved in heme uptake from the bloodstream into the cells, was also found elevated in the lungs of males. The upregulation of heme oxygenase in males indicated increased intracellular heme catabolism. Increased heme signaling resulted in the activation of heme-mediated barrier-disruptive mechanisms. Thus, hemolysis in males can be responsible for increased permeability of the lungs and early disease development. Conclusions Our study indicates the importance of barrier-disruptive mechanisms as an earlier event in the induction of pulmonary hypertension. Importantly, males are more susceptible to hemolysis and develop PH earlier than females.http://link.springer.com/article/10.1186/s13293-020-00289-5Pulmonary hypertensionHeme signalingLung permeabilitySex differenceEndothelial barrier function |
| spellingShingle | Olga Rafikova Joel James Cody A. Eccles Sergey Kurdyukov Maki Niihori Mathews Valuparampil Varghese Ruslan Rafikov Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability Biology of Sex Differences Pulmonary hypertension Heme signaling Lung permeability Sex difference Endothelial barrier function |
| title | Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability |
| title_full | Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability |
| title_fullStr | Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability |
| title_full_unstemmed | Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability |
| title_short | Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability |
| title_sort | early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability |
| topic | Pulmonary hypertension Heme signaling Lung permeability Sex difference Endothelial barrier function |
| url | http://link.springer.com/article/10.1186/s13293-020-00289-5 |
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