Pressure Load: The Main Factor for Altered Gene Expression in Right Ventricular Hypertrophy in Chronic Hypoxic Rats

Baandrup, Jonas; Markvardsen, Lars Kjøbsted; Peters, Christian Daugaard; Schou, Uffe K.; Jensen, Jens Ledet; Magnusson, Nils E.; Ørntoft, Torben F.; Kruhøffer, Mogens; Simonsen, Ulf

doi:10.1371/journal.pone.0015859

Cited by 30 publications

(33 citation statements)

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“…32 Independent studies from our lab and others have suggested that TG2mediated fibrosis is implicated in several physiological conditions that are associated with enhanced tissue glycolysis and metabolic dysfunction. 32 Independent studies from our lab and others have suggested that TG2mediated fibrosis is implicated in several physiological conditions that are associated with enhanced tissue glycolysis and metabolic dysfunction.…”

Section: Discussionmentioning

confidence: 97%

Glycolysis regulated transglutaminase 2 activation in cardiopulmonary fibrogenic remodeling

et al. 2019

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The pathophysiology of pulmonary hypertension (PH) and heart failure (HF) includes fibrogenic remodeling associated with the loss of pulmonary arterial (PA) and cardiac compliance. We and others have previously identified transglutaminase 2 (TG2) as a participant in adverse fibrogenic remodeling. However, little is known about the biologic mechanisms that regulate TG2 function. We examined physiological mouse models of experimental PH, HF, and type 1 diabetes that are associated with altered glucose metabolism/glycolysis and report here that TG2 expression and activity are elevated in pulmonary and cardiac tissues under all these conditions. We additionally used PA adventitial fibroblasts to test the hypothesis that TG2 is an intermediary between enhanced tissue glycolysis and fibrogenesis. Our in vitro results show that glycolytic enzymes and TG2 are upregulated in fibroblasts exposed to high glucose, which stimulates cellular glycolysis as measured by Seahorse analysis. We examined the relationship of TG2 to a terminal glycolytic enzyme, pyruvate kinase M2 (PKM2), and found that PKM2 regulates glucose‐induced TG2 expression and activity as well as fibrogenesis. Our studies further show that TG2 inhibition blocks glucose‐induced fibrogenesis and cell proliferation. Our findings support a novel role for glycolysis‐mediated TG2 induction and tissue fibrosis associated with experimental PH, HF, and hyperglycemia.

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Section: Discussionmentioning

confidence: 97%

Glycolysis regulated transglutaminase 2 activation in cardiopulmonary fibrogenic remodeling

et al. 2019

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“…A blood sample was collected in a microcapillary tube and centrifuged (International equipment company, micro-capillary centrifuge model M B) for three hours as previously described [36].…”

Section: Methodsmentioning

confidence: 99%

Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in KCa2.3 and KCa3.1 Channels

et al. 2014

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ObjectiveIn vascular biology, endothelial KCa2.3 and KCa3.1 channels contribute to arterial blood pressure regulation by producing membrane hyperpolarization and smooth muscle relaxation. The role of KCa2.3 and KCa3.1 channels in the pulmonary circulation is not fully established. Using mice with genetically encoded deficit of KCa2.3 and KCa3.1 channels, this study investigated the effect of loss of the channels in hypoxia-induced pulmonary hypertension.Approach and ResultMale wild type and KCa3.1−/−/KCa2.3T/T(+DOX) mice were exposed to chronic hypoxia for four weeks to induce pulmonary hypertension. The degree of pulmonary hypertension was evaluated by right ventricular pressure and assessment of right ventricular hypertrophy. Segments of pulmonary arteries were mounted in a wire myograph for functional studies and morphometric studies were performed on lung sections. Chronic hypoxia induced pulmonary hypertension, right ventricular hypertrophy, increased lung weight, and increased hematocrit levels in either genotype. The KCa3.1−/−/KCa2.3T/T(+DOX) mice developed structural alterations in the heart with increased right ventricular wall thickness as well as in pulmonary vessels with increased lumen size in partially- and fully-muscularized vessels and decreased wall area, not seen in wild type mice. Exposure to chronic hypoxia up-regulated the gene expression of the KCa2.3 channel by twofold in wild type mice and increased by 2.5-fold the relaxation evoked by the KCa2.3 and KCa3.1 channel activator NS309, whereas the acetylcholine-induced relaxation - sensitive to the combination of KCa2.3 and KCa3.1 channel blockers, apamin and charybdotoxin - was reduced by 2.5-fold in chronic hypoxic mice of either genotype.ConclusionDespite the deficits of the KCa2.3 and KCa3.1 channels failed to change hypoxia-induced pulmonary hypertension, the up-regulation of KCa2.3-gene expression and increased NS309-induced relaxation in wild-type mice point to a novel mechanism to counteract pulmonary hypertension and to a potential therapeutic utility of KCa2.3/KCa3.1 activators for the treatment of pulmonary hypertension.

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“…More recently, Baandrup et al [ 58 ] showed that the expression in the RV of the same 172 genes participating in fatty acid oxidation and the glycerol channel was altered in the chronic hypoxia or rats with banding of the pulmonary trunk (PTB). Only 11 genes (e.g.…”

Section: The Right Ventricle In Animals At High Altitudementioning

confidence: 99%

Right Ventricle and High Altitude

Richalet

Pichon

2014

The Right Heart

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At high altitude, as hypoxia induces pulmonary vasoconstriction and increases ipulmonary arterial pressure, right ventricular (RV) function will be affected. The right ventricular function may be affected directly by the hypoxaemic challenge or indirectly through a pressure overload due, in turn to changes in the pulmonary circulation. Both animal and human studies show that moderate or transient hypoxia results in adaptive changes in right ventricle that are reversible with re-exposure to normoxic conditions and RV dysfunction is mainly due to mechanical overload from the pulmonary circulation. When hypoxia is more severe or more prolonged, it may directly impact ventricular diastolic or systolic function through mechanisms that remain to be unraveled. Chronic exposure to hypoxia in high-altitude natives suffering from Monge's disease may lead to RV hypertrophy, RV failure and overall cardiac failure. The adrenergic system may be involved, as well as HIF, PKC or phospholamban. More studies using the latest imaging technology should give us a better understanding of RV systolic and diastolic function in humans exposed to altitude hypoxia including acute, chronic or chronic intermittent hypoxia.

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Pressure Load: The Main Factor for Altered Gene Expression in Right Ventricular Hypertrophy in Chronic Hypoxic Rats

Cited by 30 publications

References 48 publications

Glycolysis regulated transglutaminase 2 activation in cardiopulmonary fibrogenic remodeling

Glycolysis regulated transglutaminase 2 activation in cardiopulmonary fibrogenic remodeling

Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in KCa2.3 and KCa3.1 Channels

Right Ventricle and High Altitude

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