Statins inhibit matrix metalloproteinase release from human lung fibroblasts

Kamio, Koichiro; Liu, Xiangde; Sugiura, Hiroaki; Togo, Shinsaku; Kawasaki, Shin; Wang, X.; Ahn, Yo Han; Hogaboam, Cory M.; Rennard, Stephen I.

doi:10.1183/09031936.00134707

Cited by 45 publications

(27 citation statements)

References 48 publications

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“…Second, the upregulation of MMP-2 and -9 specifically is interesting as these proteases, known as gelatinase A and B, are zinc-dependent endopeptidases with similar structures and therefore may be potential targets for treatment 39. Indeed, statins are reported to reduce MMP-2 and -9 production by human vascular smooth muscle cells40 and MMP-9 secretion by lung fibroblasts41 and macrophages 42. Novel anti-inflammatory compounds such as p38 mitogen-activated protein kinase inhibitors specifically target activation and production of MMPs and have been shown to reduce MMP-9 release 43.…”

Section: Discussionmentioning

confidence: 99%

Systemic elastin degradation in chronic obstructive pulmonary disease

Maclay

McAllister

Rabinovich

et al. 2012

Thorax

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Background Development of emphysema and vascular stiffness in chronic obstructive pulmonary disease (COPD) may be due to a common mechanism of susceptibility to pulmonary and systemic elastin degradation. Objectives To investigate whether patients with COPD have evidence of systemic elastin degradation in the skin. Methods The authors measured cutaneous elastin degradation using immunohistochemistry (percentage area of elastin fibres) in sun-exposed (exposed) and nonsun-exposed (non-exposed) skin biopsies in 16 men with COPD and 15 controls matched for age and cigarette smoke exposure. Quantitative PCR of matrix metalloproteinase (MMP)-2, -9, -12 and tissue inhibitor of metalloproteinase-1 mRNA and zymography for protein expression of MMP-2 and -9 were performed on homogenised skin. Arterial stiffness and emphysema severity were measured using carotid-femoral pulse wave velocity and quantitative CT scanning. Results Skin elastin degradation was greater in exposed and non-exposed skin of patients with COPD compared with controls (exposed, mean (SD); 43.5 (12.1)% vs 26.3 (6.9)%, p<0.001; non-exposed 22.4 (5.2)% vs 18.1 (4.3)%, p¼0.02). Cutaneous expression of MMP-9 mRNA and proMMP-9 concentrations was increased in exposed skin of COPD patients (p¼0.004 and p¼0.02, respectively) and was also associated with increased skin elastin degradation (r¼0.62, p<0.001 and r¼0.47, p¼0.01, respectively). In the entire cohort of exsmokers, cutaneous elastin degradation was associated with emphysema severity, FEV 1 and pulse wave velocity. Conclusions Patients with COPD have increased skin elastin degradation compared with controls, which is related to emphysema severity and arterial stiffness. Systemic elastin degradation due to increased proteolytic activity may represent a novel shared mechanism for the pulmonary, vascular and cutaneous features of COPD.

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Section: Discussionmentioning

confidence: 99%

Systemic elastin degradation in chronic obstructive pulmonary disease

Maclay

McAllister

Rabinovich

et al. 2012

Thorax

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“…Statins influence metalloproteinases, enzymes that promote cell transformation. 6 Additionally, statins inhibit the production of dolichol, ubiquinol, farnesol and geranylgeraniol, all of which are involved in angiogenesis, tumor cell proliferation, and differentiation. 12,13 These molecular mechanisms probably explain the reduction in incidence of cancer in heart transplant patients on statin therapy.…”

Section: Discussionmentioning

confidence: 99%

Impact of Statin Use After Heart Transplantation

Vallakati

Reddy

Dunlap

et al. 2016

Circ: Heart Failure

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Background— Although various studies revealed the beneficial effects of statins in post–cardiac transplant patients, these were relatively small and low-powered studies. We performed a meta-analysis of published studies to evaluate the role of statins in post–cardiac transplant patients, specifically examining the effects on hemodynamically significant/fatal graft rejection, coronary vasculopathy, terminal cancer, and overall survival. Methods and Results— We searched PubMed, Cochran CENTRAL, and Web of Science databases using the search terms “cardiac transplant” or “heart transplant,” and “statin” for a literature search. A random-effects model with Mantel–Haenszel method was used to pool the data. We identified 10 studies, 4 randomized controlled trials, and 6 nonrandomized studies, which compared outcomes in heart transplant recipients undergoing statin therapy to statin-naive patients. A pooled analysis of 9 studies reporting mortality revealed that the use of statins was associated with significant reduction in all-cause mortality (odds ratio, 0.26; 95% confidence interval, 0.20–0.35; P <0.0001). Statins also decreased the odds of hemodynamically significant/fatal rejection (odds ratio, 0.37; 95% confidence interval, 0.21–0.65; P =0.0005), incidence of coronary vasculopathy (odds ratio, 0.33; 95% confidence interval, 0.16–0.68; P =0.003), and terminal cancer (odds ratio, 0.30; 95% confidence interval, 0.15–0.63; P =0.002). Conclusions— The evidence from a pooled analysis suggests that statins improve survival in heart transplant recipients. Statins may prevent fatal rejection episodes, decrease terminal cancer risk, and reduce the incidence of coronary vasculopathy. Additional prospective studies are needed to further investigate and explain this association.

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“…Among other effects, statins were shown to decrease MMPs expression and activities (Kamio et al 2010;Souza-Costa et al 2007a;Souza-Costa et al 2007b;Massaro et al 2010), and there is also experimental evidence that statins downregulate MMPs in different cell types in vitro (Barter et al 2010;Bellosta et al 1998;Ikeda et al 2000;Luan et al 2003;Massaro et al 2010).…”

Section: Introductionmentioning

confidence: 97%

Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells

Izidoro-Toledo

Guimaraes

Belo

et al. 2011

Naunyn-Schmiedeberg's Arch Pharmacol

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Statins exert anti-inflammatory effects and downregulate matrix metalloproteinases (MMPs) expression, thus contributing to restore cardiovascular homeostasis in cardiovascular diseases. We aimed at comparing the effects of different statins (simvastatin, atorvastatin, and pravastatin) on MMP-2, MMP-9, tissue inhibitors of metalloproteinases (TIMP)-1, TIMP-2, and MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios released by human umbilical vein endothelial cells (HUVEC) stimulated by phorbol myristate acetate (PMA). HUVECs were incubated with statins (0.1-10 μM) for 12 h before stimulation with PMA 100 nM. Monolayers were used to perform cell viability assays and the supernatants were collected to determine MMPs and TIMPs levels by gelatin zymography and/or enzyme immunoassay. While treatment with PMA increased MMP-9 and TIMP-1 levels (by 556% and 159%, respectively; both P < 0.05), it exerted no effects on MMP-2 and TIMP-2 levels. Simvastatin and atorvastatin, but not pravastatin, attenuated PMA-induced increases in MMP-9 levels (P < 0.05). Only atorvastatin decreased baseline MMP-2 levels significantly (P < 0.05). We found no effects on TIMP-2 levels. Simvastatin and atorvastatin, but not pravastatin, decreased MMP-9/TIMP-1 ratio significantly (both P < 0.05), whereas atorvastatin and pravastatin, but not simvastatin, decreased MMP-2/TIMP-2 ratio significantly (both P < 0.05). Our data support the notion that statins with different physicochemical features exert variable effects on MMP/TIMP ratios (which reflect net MMP activity). Our results suggest that more lipophilic statins (simvastatin and atorvastatin), but not the hydrophilic statin pravastatin, downregulate net MMP-9 activity. However, atorvastatin and pravastatin may downregulate net MMP-2 activity. The clinical implications of the present findings deserve further investigation.

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Statins inhibit matrix metalloproteinase release from human lung fibroblasts

Cited by 45 publications

References 48 publications

Systemic elastin degradation in chronic obstructive pulmonary disease

Systemic elastin degradation in chronic obstructive pulmonary disease

Impact of Statin Use After Heart Transplantation

Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells

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