Calpain mediates pulmonary vascular remodeling in rodent models of pulmonary hypertension, and its inhibition attenuates pathologic features of disease

Ma, Wanli; Han, Wei; Greer, Peter A.; Tuder, Rubin M.; Toque, Haroldo A.; Wang, Kevin; Caldwell, Robert W.; Su, Yunchao

doi:10.1172/jci57734

Cited by 95 publications

(116 citation statements)

References 79 publications

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“…Both bone morphogenetic proteins (BMPs) and TGF-β isoforms that mediate signaling are believed to be involved in PA remodeling in PAH (34). Consistent with previous reports (35,36), we observed that hypoxia suppressed the expression of the inhibitor of differentiation 1 (ID1) (Supplemental Figure 9A), a downstream target of the BMP receptor 2 pathway, and hypoxia induced the expression of PAI-1, a target of TGF-β1 signaling (Supplemental Figure 9B), in mPASMCs. Meanwhile, Ep3 deletion attenuated hypoxia-stimulated PAI-1 expression without significant influence on ID1 expression, indicating that the EP3 receptor may modulate TGF-β1 signaling in mPASMCs.…”

Section: Resultssupporting

confidence: 84%

EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling

Lü

Zuo

et al. 2015

J. Clin. Invest.

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Section: Resultssupporting

confidence: 84%

EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling

Lü

Zuo

et al. 2015

J. Clin. Invest.

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“…For calpain inhibitor studies, calpain inhibitor III was injected once daily for 7 days intraperitoneally (30 mg/kg body weight) starting the same day as NTS injection. Control mice received an equal volume of PEG400/DMSO (65,66). Mice urine samples were obtained on days 0 and 7 and were evaluated for calpain activity following NTS injection.…”

Section: Methodsmentioning

confidence: 99%

Podocyte-associated talin1 is critical for glomerular filtration barrier maintenance

Tian¹,

Kim²,

Monkley³

et al. 2014

J. Clin. Invest.

124

170

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Podocytes are specialized actin-rich epithelial cells that line the kidney glomerular filtration barrier. The interface between the podocyte and the glomerular basement membrane requires integrins, and defects in either α 3 or β 1 integrin, or the α 3 β 1 ligand laminin result in nephrotic syndrome in murine models. The large cytoskeletal protein talin1 is not only pivotal for integrin activation, but also directly links integrins to the actin cytoskeleton. Here, we found that mice lacking talin1 specifically in podocytes display severe proteinuria, foot process effacement, and kidney failure. Loss of talin1 in podocytes caused only a modest reduction in β 1 integrin activation, podocyte cell adhesion, and cell spreading; however, the actin cytoskeleton of podocytes was profoundly altered by the loss of talin1. Evaluation of murine models of glomerular injury and patients with nephrotic syndrome revealed that calpain-induced talin1 cleavage in podocytes might promote pathogenesis of nephrotic syndrome. Furthermore, pharmacologic inhibition of calpain activity following glomerular injury substantially reduced talin1 cleavage, albuminuria, and foot process effacement. Collectively, these findings indicate that podocyte talin1 is critical for maintaining the integrity of the glomerular filtration barrier and provide insight into the pathogenesis of nephrotic syndrome.

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“…Four epoxyeicosatrienoic acid (EET) regioisomers (5,8,11,(12)(13)(14) are the metabolites of AA by the cytochrome 450 (CYP) monooxygenase pathway (9,10). Similar to many eicosanoids, EETs have multiple biological functions, including the regulation of cardiovascular inflammation, the reduction of blood pressure, as well as anti-atherosclerotic functions in multiple model systems.…”

Section: Introductionmentioning

confidence: 99%

“…Sturrock et al (7) demonstrated that TGF-β1 is abundantly expressed in patients with pulmonary hypertension, and promotes pulmonary artery smooth muscle cell (PASMC) proliferation in low serum medium. The inhibition of TGF-β1 signaling has been demonstrated to attenuate pulmonary vascular remodeling and increase right ventricular pressure in animal models (8).…”

Section: Introductionmentioning

confidence: 99%

EETs and CYP2J2 inhibit TNF-α-induced apoptosis in pulmonary artery endothelial cells and TGF-β1-induced migration in pulmonary artery smooth muscle cells

Feng

Zhao

et al. 2013

International Journal of Molecular Medicine

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Abstract. Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids (EETs) have multiple biological functions in cardiovascular homeostasis. The anti-inflammatory, anti-migratory and pro-proliferative effects of EETs suggest a possible beneficial role for EETs in the apoptosis, proliferation and migration of pulmonary vascular cells. In this study, we investigated the effects of exogenous EETs and cytochrome P450 2J2 (CYP2J2) overexpression on tumor necrosis factor-α (TNF-α)-induced pulmonary artery endothelial cell (PAEC) apoptosis, and transforming growth factor-β1 (TGF-β1)-induced pulmonary artery smooth muscle cell (PASMC) proliferation and migration. PAECs and PASMCs were cultured from porcine pulmonary arteries. Our findings indicated that EETs or CYP2J2 overexpression significantly protected the PAECs from TNF-α-induced apoptosis, as evaluated by cell viability and flow cytometry. Two mechanisms were found to be involved in these important protective effects: firstly, EETs and CYP2J2 overexpression inhibited the decrease in the expression of the antiapoptotic proteins, Bcl-2 and Bcl-xL, as well as the increase in the expression of the pro-apoptotic protein, Bax, mediated by TNF-α; secondly, they activated the phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) signaling pathways. We also found that 11,12-EET and 14,15-EET significantly inhibited TGF-β1-stimulated PASMC migration. However, EETs did not suppress TGF-β1-induced PASMC proliferation in vitro. These data may represent a novel approach to mitigate pulmonary vascular remodeling in diseases, such as pulmonary arterial hypertension. IntroductionPulmonary vascular remodeling is one of the most important pathological changes in patients with pulmonary arterial hypertension (PAH). Endothelial cells are recognized as major regulators of vascular function. The balance between endothelial cell survival and death is critical in various processes, such as the regulation of vasoconstriction and vasodilation, smooth muscle cell growth and migration, thrombotic formation, intravascular inflammation and vascular remodeling (1,2). Inflammation is one of the main features of PAH, and circulating levels of cytokines, including tumor necrosis factor-α (TNF-α), are elevated in patients with PAH (3,4). During the early stages of vascular remodeling, inflammatory infiltration directly participates in the apoptosis of endothelial cells. Considerable experimental evidence suggests that the apoptosis of endothelial cells induces the release of mediators, in particular, transforming growth factor-β1 (TGF-β1), which induces the proliferation and migration of vascular smooth muscle cells (5,6). Sturrock et al (7) demonstrated that TGF-β1 is abundantly expressed in patients with pulmonary hypertension, and promotes pulmonary artery smooth muscle cell (PASMC) proliferation in low serum medium. The inhibition of TGF-β1 signaling has been demonstrated to attenuate pulmonary vascular remodeling and increase right ventricular pressure in anim...

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Calpain mediates pulmonary vascular remodeling in rodent models of pulmonary hypertension, and its inhibition attenuates pathologic features of disease

Cited by 95 publications

References 79 publications

EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling

EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling

Podocyte-associated talin1 is critical for glomerular filtration barrier maintenance

EETs and CYP2J2 inhibit TNF-α-induced apoptosis in pulmonary artery endothelial cells and TGF-β1-induced migration in pulmonary artery smooth muscle cells

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