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MitoQ in (1) pulmonary arterial hypertension and (2) progressive optic neuropathy

mitoq pulmonary arterial hypertension; progressive optic neuropathy

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Posted 02 September 2019 - 11:18 PM

Am J Physiol Lung Cell Mol Physiol. 2019 Aug 28. doi: 10.1152/ajplung.00396.2018. [Epub ahead of print]


Regulation of Mitochondrial Fragmentation in Microvascular Endothelial Cells Isolated from the Su5416/Hypoxia model of Pulmonary Arterial Hypertension.


Author information


1 Pulmonary / Critical Care, Johns Hopkins University, United States. 2 Pulmonary & Critical Care medicine, Johns Hopkins University, Johns Hopkins University. 3 Pulmonary / Critical Care Medicine, Johns Hopkins University. 4 Johns Hopkins, United States. 5 Physiology, Johns Hopkins University. 6 Pathology, Johns Hopkins University, United States. 7 Medicine, Johns Hopkins University School of Medicine, United States. 8 Pulmonary & Critical Care Medicine, Johns Hopkins University, United States.



Pulmonary arterial hypertension (PAH) is a morbid disease characterized by progressive right ventricle (RV) failure due to elevated pulmonary artery pressures (PAP). In PAH, histologically complex vaso-occlusive lesions in the pulmonary vasculature contribute to elevated PAP. However, the mechanisms underlying dysfunction of the microvascular endothelial cells (MVECs) that comprise a significant portion of these lesions are not well understood. We recently showed that MVECs isolated from the rat Sugen/Hypoxia (SuHx) experimental model of PAH (SuHx-MVECs) exhibit increases in: migration/proliferation, mitochondrial ROS (mtROS) production, intracellular calcium levels ([Ca2+]i) and mitochondrial fragmentation. Furthermore, quenching mtROS with the targeted antioxidant MitoQ attenuated basal [Ca2+]I, migration and proliferation; however, whether increased mtROS was associated with increased [Ca2+]iand/or changes in mitochondrial morphology was not clear. To better understand this relationship, we measured changes in mitochondrial morphology at baseline and following inhibition of mtROS with the targeted antioxidant MitoQ and Ca2+ entry, by inhibiting the Ca2+ channel TRPV4. Quenching mtROS or inhibiting TRPV4 attenuated fragmentation in SuHx-MVECs. Conversely, inducing mtROS production in MVECs from normoxic rats (N-MVECs) increased fragmentation. Ca2+ entry induced by treatment with the TRPV4 agonist, GSK1017920A, was significantly increased in SuHx-MVECs and was attenuated with MitoQ treatment. Basal and maximal respiration were depressed in SuHx-MVECs, and inhibiting mtROS but not TRPV4 improved respiration in these cells. Our data show that, in SuHx-MVECs, mtROS production promotes: a) TRPV4-mediated increases in [Ca2+]i; b) mitochondrial fission and c) decreased mitochondrial respiration, suggesting an important role for mtROS in driving MVEC dysfunction in PAH.


PAH; calcium; endothelium; mitochondria

PMID:   31461316   DOI:   10.1152/ajplung.00396.2018 
Invest Ophthalmol Vis Sci. 2019 Aug 1;60(10):3613-3624. doi: 10.1167/iovs.19-27542.

Mitochondrial-Targeted Antioxidants Attenuate TGF-β2 Signaling in Human Trabecular Meshwork Cells.


Rao VR1,2Lautz JD1,3Kaja S1,2,4Foecking EM1,5Lukács E1,2Stubbs EB Jr1,2.

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1 Research Service, Department of Veterans Affairs, Edward Hines Jr. VA Hospital, Hines, Illinois, United States. 2 Department of Ophthalmology, Loyola University Health Science Division, Maywood, Illinois, United States. 3 Program of Neuroscience, Loyola University Health Science Division, Maywood, Illinois, United States. 4 Department of Molecular Pharmacology and Therapeutics, Loyola University Health Science Division, Maywood, Illinois, United States. 5 Department of Otolaryngology Head and Surgery, Loyola University Health Science Division, Maywood, Illinois, United States.





POAG is a progressive optic neuropathy that is currently the leading cause of irreversible blindness worldwide. While the underlying cause of POAG remains unclear, TGF-β2-dependent remodeling of the extracellular matrix (ECM) within the trabecular meshwork ™ microenvironment is considered an early pathologic consequence associated with impaired aqueous humor (AH) outflow and elevated IOP. Early studies have also demonstrated markedly elevated levels of oxidative stress markers in AH from POAG patients along with altered expression of antioxidant defenses. Here, using cultured primary or transformed human TM cells, we investigated the role oxidative stress plays at regulating TGF-β2-mediated remodeling of the ECM.




Primary or transformed (GTM3) human TM cells conditioned in serum-free media were incubated in the absence or presence of TGF-β2 and relative changes in intracellular reactive oxygen species (ROS) were measured using oxidation-sensitive fluorogenic dyes CellROX green or 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate (carboxy-H2DCFDA). TGF-β2-mediated changes in the content of connective tissue growth factor (CTGF) and collagen types 1α1 (COL1A1) and 4α1 (COL4A1) mRNA or collagens I and IV isoform proteins were determined in the absence or presence of mitochondrial-targeted antioxidants (XJB-5-131 or MitoQ) and quantified by quantitative PCR or by immunoblot and immunocytochemistry. Smad-dependent canonic signaling was determined by immunoblot, whereas Smad-dependent transcriptional activity was quantified using a Smad2/3-responsive SBE-luciferase reporter assay.




Primary or transformed human TM cells cultured in the presence of TGF-β2 (5 ng/mL; 2 hours) exhibited marked increases in CellROX or fluorescein fluorescence. Consistent with previous reports, challenging cultured human TM cells with TGF-β2 elicited measurable increases in regulated Smad2/3 signaling as well as increases in CTGF, COL1A1, and COL4A1 mRNA and collagen protein content. Pretreating human TM cells with mitochondrial-targeted antioxidants XJB-5-131 (10 μM) or MitoQ (10 nM) attenuated TGF-β2-mediated changes in Smad-dependent transcriptional activity.




The multifunctional profibrotic cytokine TGF-β2 elicits a marked increase in oxidative stress in human TM cells. Mitochondrial-targeted antioxidants attenuate TGF-β2-mediated changes in Smad-dependent transcriptional activity, including marked reductions in CTGF and collagen isoform gene and protein expression. These findings suggest that mitochondrial-targeted antioxidants, when delivered directly to the TM, exhibit potential as a novel strategy by which to slow the progression of TGF-β2-mediated remodeling of the ECM within the TM.


PMID:   31433458   DOI:   10.1167/iovs.19-27542


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