Hemolysis-induced Lung Vascular Leakage Contributes to the Development of Pulmonary Hypertension

Rafikova, Olga; Williams, Elissa R; McBride, Matthew L.; Zemskova, Marina; Srivastava, Anup; Nair, Vineet; Desai, Ankit A.; Langlais, Paul; Zemskov, Evgeny A.; Simon, Marc A.; Mandarino, Lawrence J.; Rafikov, Ruslan

doi:10.1165/rcmb.2017-0308oc

Cited by 36 publications

(48 citation statements)

References 47 publications

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“…Besides heme, ferrylHb but not Hb or metHb induces upregulation of adhesion molecules in ECs, but interestingly, this response is not dependent on TLR4 activation (16). Increased endothelial permeability contributes to inflammatory cell extravasation upon hemolysis, and previous studies showed that ferrylHb and free heme induce the loss of endothelial integrity (16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 92%

The Role of Hemoglobin Oxidation Products in Triggering Inflammatory Response Upon Intraventricular Hemorrhage in Premature Infants

et al. 2020

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Intraventricular hemorrhage (IVH) is a frequent complication of prematurity that is associated with high neonatal mortality and morbidity. IVH is accompanied by red blood cell (RBC) lysis, hemoglobin (Hb) oxidation, and sterile inflammation. Here we investigated whether extracellular Hb, metHb, ferrylHb, and heme contribute to the inflammatory response after IVH. We collected cerebrospinal fluid (CSF) (n = 20) from premature infants with grade III IVH at different time points after the onset of IVH. Levels of Hb, metHb, total heme, and free heme were the highest in CSF samples obtained between days 0 and 20 after the onset of IVH and were mostly non-detectable in CSF collected between days 41 and 60 of post-IVH. Besides Hb monomers, we detected cross-linked Hb dimers and tetramers in post-IVH CSF samples obtained in days 0-20 and 21-40, but only Hb tetramers were present in CSF samples obtained after 41-60 days. Vascular cell adhesion molecule-1 (VCAM-1) and interleukin-8 (IL-8) levels were higher in CSF samples obtained between days 0 and 20 than in CSF collected between days 41 and 60 of post-IVH. Concentrations of VCAM-1, intercellular adhesion molecule-1 (ICAM-1), and IL-8 strongly correlated with total heme levels in CSF. Applying the identified heme sources on human brain microvascular endothelial cells revealed that Hb oxidation products and free heme contribute to the inflammatory response. We concluded that RBC lysis, Hb oxidation, and heme release are important components of the inflammatory response in IVH. Pharmacological interventions targeting cellfree Hb, Hb oxidation products, and free heme could have potential to limit the neuroinflammatory response following IVH.

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Section: Introductionmentioning

confidence: 92%

The Role of Hemoglobin Oxidation Products in Triggering Inflammatory Response Upon Intraventricular Hemorrhage in Premature Infants

et al. 2020

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“…Fourteen days post-MCT/vehicle treatment; animals were anesthetized with Inactin (Sigma-Aldrich, T133) at the dosage of 100 mg/kg, i.p. A customized pressure transducer catheter (SPR-513, Millar Instruments, Houston, TX) was inserted through the right jugular vein and advanced into the right ventricle (RV) to monitor right ventricular systolic pressure (RVSP) and right ventricular diastolic pressure (RVDP) as described previously [17]. Briefly, the pressure transducer catheter was connected to a Millar Transducer Control Unit TC-510 and PL3504 PowerLab 4/35 data acquisition system (AD Instruments, Colorado Springs, CO) to continuously record RV pressure under small animal ventilator system (Harvard Rodent Ventilator-683; Harvard Apparatus, South Natick, MA).…”

Section: Hemodynamic Measurements and Sample Collectionmentioning

confidence: 99%

“…Recently, we have reported that patients with PH have increased levels of circulating free hemoglobin (Hb), a marker of hemolysis, which strongly correlated with the clinical characteristics of PH progression [17]. In the SU/Hx model, hemolysis was associated with an increased heme-mediated endothelial barrier dysfunction and formation of perivascular edema.…”

Section: Introductionmentioning

confidence: 99%

Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability

et al. 2020

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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.

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“…Akt nitration was induced by treatment with 3-morpholinosyndnomine (SIN-1) (1 mM) for 1 h. NP pretreatment groups were treated with 1 µM NP for 30 min, and then cells were washed in PBS and treated with SIN-1 for 1 h. All treatments were accompanied by including controls with the corresponding vehicle. After treatment, the cells were washed in PBS and lysed in RIPA buffer containing protease and phosphatase inhibitor cocktail [17].…”

Section: Sin-1 Induced Akt Nitration Assaymentioning

confidence: 99%

Antioxidant-Conjugated Peptide Attenuated Metabolic Reprogramming in Pulmonary Hypertension

et al. 2020

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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.

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Hemolysis-induced Lung Vascular Leakage Contributes to the Development of Pulmonary Hypertension

Cited by 36 publications

References 47 publications

The Role of Hemoglobin Oxidation Products in Triggering Inflammatory Response Upon Intraventricular Hemorrhage in Premature Infants

The Role of Hemoglobin Oxidation Products in Triggering Inflammatory Response Upon Intraventricular Hemorrhage in Premature Infants

Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability

Antioxidant-Conjugated Peptide Attenuated Metabolic Reprogramming in Pulmonary Hypertension

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