Involvement of Calpain-Calpastatin in Cigarette Smoke–Induced Inhibition of Lung Endothelial Nitric Oxide Synthase

Cui, Zhaoqiang; Han, Zhaosheng; Li, Zhaozhong; Hu, Han-Bo; Patel, Jawaharlal M.; Antony, Veena B.; Block, Edward R.; Su, Yunchao

doi:10.1165/rcmb.2005-0046oc

Cited by 16 publications

(11 citation statements)

References 47 publications

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“…However, infection of PAEC with adenovirus containing a fulllength calpastatin cDNA resulted in a dramatic decrease in calpain activity as measured by detecting calcium-dependent cleavage of resorufin-labeled casein in vitro and the calpain-mediated degradation of natural substrate spectrin in intact cells. However, the protein contents of calpain-1 and calpain-2 did not change in calpastatin-overexpressed cells, suggesting that the decrease in calpain activity is caused by the inhibitory effect of calpastatin on calpain (27). Corresponding to the changes in calpain activity, infection of PMEC with adenovirus containing full-length porcine calpastatin cDNA caused decreases in endothelial monolayer wound repair and endothelial tube formation as well as in VEGF-induced increases in monolayer wound repair and tube formation (Fig.…”

Section: Effect Of Calpastatin Overexpression On Calpain Activity Enmentioning

confidence: 92%

“…The inserts excised from NheI/SalI sites of calpastatin-CFP were used to construct recombinant adenoviruses containing tetracycline (Tet) -regulated gene inserts according to the manufacturer's instructions. After package, propagation, pu-rification, and titration, the resulting adenoviruses and Adeno-X Tet-Off regulatory virus were used to coinfect PMEC as previously reported by us (27).…”

Section: Construction and Transient Expression Of An Adenoviral Vectomentioning

confidence: 99%

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Calpain‐2 regulation of VEGF‐mediated angiogenesis

Cui

et al. 2006

FASEB j.

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Angiogenesis is a complex process involving endothelial cell migration, proliferation, and differentiation as well as tube formation. These processes are stimulated by a variety of growth factors such as vascular endothelial growth factor (VEGF). VEGF-induced cytoskeletal reorganization plays a crucial role in the angiogenic processes. In the present study, we evaluated the role of calpain in VEGF-induced angiogenesis in vitro and in vivo. Human pulmonary microvascular endothelial cells (PMEC) were incubated with VEGF (10-60 ng/ml) for 2-24 h, after which we measured calpain activities, protein contents of the calpain subunits and of calpastatin, endothelial monolayer wound repair, tube formation, and actin cytoskeleton changes. Incubation of PMEC with VEGF resulted in dose- and time-dependent increases in calpain activity and protein content of calpain-2. VEGF did not change the protein contents of calpain-1 and the small subunit or of calpastatin. Incubation of PMEC with a VEGF receptor blocker prevented the VEGF-induced increase in calpain activity. Inhibition of calpain activity by siRNA directed against calpain-2 and by overexpression of calpastatin prevented VEGF-induced increases in actin stress fibers in endothelial cells and angiogenesis. Overexpression of calpastatin also inhibits vessel formation in subcutaneous (s.c.) matrigel plugs in mice. These results indicate that calpain mediates VEGF-induced angiogenic effects by modulating actin cytoskeletal organization.

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Section: Effect Of Calpastatin Overexpression On Calpain Activity Enmentioning

confidence: 92%

Section: Construction and Transient Expression Of An Adenoviral Vectomentioning

confidence: 99%

Calpain‐2 regulation of VEGF‐mediated angiogenesis

Cui

et al. 2006

FASEB j.

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“…Our fi ndings of reduced eNOS expression and activity in the human vascular endothelium aft er exposure to SHS concur with previous reports of reduced eNOS protein and mRNA expression and its enzymatic activity after prolonged exposure to cigarette smoke extract in vitro. 24,25 Th us, direct characterization of the vascular endothelium may refl ect more accurately the extent of reduced NO availability in passive smokers than indirect assessment of endothelial function by FMD.…”

Section: Figure 1 -Expression Of Markers Of Endothelial Reactivity Imentioning

confidence: 99%

Secondhand Smoking Is Associated With Vascular Inflammation

Adams

Wan

Wei

et al. 2015

Chest

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“…Notably, calpain inhibition affects vascular constriction and relaxation of pulmonary arteries. For example, we have previously reported that calpain inhibitors decrease gene expression of eNOS (57).…”

Section: Figure 10mentioning

confidence: 99%

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

Han

Greer³

et al. 2011

J. Clin. Invest.

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100

105

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Pulmonary hypertension is a severe and progressive disease, a key feature of which is pulmonary vascular remodeling. Several growth factors, including EGF, PDGF, and TGF-β1, are involved in pulmonary vascular remodeling during pulmonary hypertension. However, increased knowledge of the downstream signaling cascades is needed if effective clinical interventions are to be developed. In this context, calpain provides an interesting candidate therapeutic target, since it is activated by EGF and PDGF and has been reported to activate TGF-β1. Thus, in this study, we examined the role of calpain in pulmonary vascular remodeling in two rodent models of pulmonary hypertension. These data showed that attenuated calpain activity in calpain-knockout mice or rats treated with a calpain inhibitor resulted in prevention of increased right ventricular systolic pressure, right ventricular hypertrophy, as well as collagen deposition and thickening of pulmonary arterioles in models of hypoxia-and monocrotaline-induced pulmonary hypertension. Additionally, inhibition of calpain in vitro blocked intracellular activation of TGF-β1, which led to attenuated Smad2/3 phosphorylation and collagen synthesis. Finally, smooth muscle cells of pulmonary arterioles from patients with pulmonary arterial hypertension showed higher levels of calpain activation and intracellular active TGF-β. Our data provide evidence that calpain mediates EGF-and PDGF-induced collagen synthesis and proliferation of pulmonary artery smooth muscle cells via an intracrine TGF-β1 pathway in pulmonary hypertension. IntroductionPulmonary hypertension is a severe and progressive disease characterized by increased pulmonary vascular resistance leading to right heart failure and death (1-3). Pulmonary vascular remodeling is an important common pathological feature of all categories of pulmonary hypertension. Accumulation of extracellular matrix, including collagen, and vascular smooth muscle cell proliferation and hypertrophy contribute to medial hypertrophy and muscularization, leading to obliteration of precapillary pulmonary arteries and sustained elevation of pulmonary arterial pressure (3, 4).Several growth factors, including EGF, PDGF, and TGF-β1, participate in the process of pulmonary vascular remodeling in patients with pulmonary hypertension and in animal models (2,(5)(6)(7)(8). For example, expression of EGF or its receptor EGFR are increased in animal models of monocrotaline-(MCT-) and hypoxia-induced pulmonary hypertension and in humans with pulmonary hypertension (8-10). Blockade of EGFR results in reductions in pulmonary pressure, right ventricular hypertrophy, and distal arterial muscularization in MCT-induced pulmonary hypertension (11). Moreover, PDGF and its receptor are upregulated in pulmonary arteries of patients with pulmonary hypertension (12, 13) and rodents exposed to chronic hypoxia and MCT (7,14,15). PDGF receptor antagonists not only prevent, but also reverse, increased

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Involvement of Calpain-Calpastatin in Cigarette Smoke–Induced Inhibition of Lung Endothelial Nitric Oxide Synthase

Cited by 16 publications

References 47 publications

Calpain‐2 regulation of VEGF‐mediated angiogenesis

Calpain‐2 regulation of VEGF‐mediated angiogenesis

Secondhand Smoking Is Associated With Vascular Inflammation

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

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