Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease

Cowan, Kyle N.; Jones, Peter; Rabinovitch, Marlene

doi:10.1172/jci6539

Cited by 262 publications

(216 citation statements)

References 46 publications

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“…17 Matrix metalloproteinase (MMP)-2, MMP-9, and tenascin-C (TN-C) were elevated in NIPAH but not in IPAH patient plasma. TN-C is activated and/or induced in multiple forms of clinical and experimental PAH [18][19][20][21][22] and may contribute to PAH via its ability to cross mod- ulate the activity of epithelial growth factor (EGF) receptors, as well as via its control of cell migration and programmed cell death. Furthermore, ENRAGE (extracellular newly identified RAGE-binding protein, S100A12) showed a 16.2-fold increase in IPAH patients and an 11.9-fold increase in NIPAH patients.…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin Upregulation in Pulmonary Arterial Hypertension

et al. 2014

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The pathophysiologic alterations of patients with pulmonary arterial hypertension (PAH) are diverse. We aimed to determine novel pathogenic pathways from circulating proteins in patients with PAH. Multianalyte profiling (MAP) was used to measure 90 specifically selected antigens in the plasma of 113 PAH patients and 51 control patients. Erythropoietin (EPO) functional activity was assessed via in vitro pulmonary artery endothelial cell networking and smooth muscle cell proliferation assays. Fifty-eight patients had idiopathic PAH, whereas 55 had other forms of PAH; 5 had heritable PAH, 18 had connective tissue disease (15 with scleroderma and 3 with lupus erythematosis), 13 had portopulmonary hypertension, 6 had PAH associated with drugs or toxins, and 5 had congenital heart disease. The plasmaantigen profile of PAH revealed increased levels of several novel biomarkers, including EPO. Immune quantitative and histochemical studies revealed that EPO not only was significantly elevated in the plasma of PAH patients but also promoted pulmonary artery endothelial cell network formation and smooth muscle cell proliferation. MAP is a hypothesis-generating approach to identifying novel pathophysiologic pathways in PAH. EPO is upregulated in the circulation and lungs of patients with PAH and may affect endothelial and smooth muscle cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Erythropoietin Upregulation in Pulmonary Arterial Hypertension

et al. 2014

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“…Medial hypertrophy caused by PASMC hyperplasia and hypertrophy in distal vessels accounts for some of the pulmonary vascular remodeling in IPAH patients (3,5,6). Identifying the factors involved in promoting PASMC proliferation could assist in the development of effective therapeutic approaches for patients with IPAH.…”

Section: Discussionmentioning

confidence: 99%

“…A central aspect of pulmonary vascular remodeling is medial hypertrophy caused by sustained pulmonary vasoconstriction (2-4), excessive pulmonary artery smooth muscle cell (PASMC) proliferation (5), and inhibited PASMC apoptosis (6, 7), resulting in a narrowed vascular lumen and increased PVR. Although its etiology remains unclear, elevated levels of circulating mitogens, dysfunction or down-regulation of receptors and ion channels, upregulation of transporters, and heightened activity of elastases and glycoproteins have been implicated in IPAH (5,6,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) Transient receptor potential (TRP) channel genes may encode subunits that form receptor-(ROC) and store-(SOC) operated Ca 2ϩ channels in many cell types, including PASMC and pulmonary artery endothelial cells (PAEC) (28,(30)(31)(32)(33)(34). Ca 2ϩ entry through ROC and SOC increases [Ca 2ϩ ] cyt , allowing for phosphorylation of signal transduction proteins and transcription factors (23,24,(35)(36)(37)(38), that are essential for the progression of the cell cycle (21).…”

mentioning

confidence: 99%

“…A central aspect of pulmonary vascular remodeling is medial hypertrophy caused by sustained pulmonary vasoconstriction (2)(3)(4), excessive pulmonary artery smooth muscle cell (PASMC) proliferation (5), and inhibited PASMC apoptosis (6,7), resulting in a narrowed vascular lumen and increased PVR. Although its etiology remains unclear, elevated levels of circulating mitogens, dysfunction or down-regulation of receptors and ion channels, upregulation of transporters, and heightened activity of elastases and glycoproteins have been implicated in IPAH (5,6,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

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confidence: 99%

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Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension

Fantozzi

Remillard

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

395

366

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Pulmonary vascular medial hypertrophy caused by excessive pulmonary artery smooth muscle cell (PASMC) proliferation is a major cause for the elevated pulmonary vascular resistance in patients with idiopathic pulmonary arterial hypertension (IPAH). Increased Ca 2؉ influx is an important stimulus for PASMC proliferation. Transient receptor potential (TRP) channel genes encode Ca 2؉ channels that are responsible for Ca 2؉ entry during cell proliferation. Normal human PASMC expressed multiple canonical TRP (TRPC) isoforms; TRPC6 was highly expressed and TRPC3 was minimally expressed. The protein expression of TRPC6 in normal PASMC closely correlated with the expression of Ki67, suggesting that TRPC6 expression is involved in the transition of PASMC from quiescent phase to mitosis. In lung tissues and PASMC from IPAH patients, the mRNA and protein expression of TRPC3 and -6 were much higher than in those from normotensive or secondary pulmonary hypertension patients. Inhibition of TRPC6 expression with TRPC6 small interfering RNA markedly attenuated IPAH-PASMC proliferation. These results demonstrate that expression of TRPC channels correlates with the progression of the cell cycle in PASMC. TRPC channel overexpression may be partially responsible for the increased PASMC proliferation and pulmonary vascular medial hypertrophy in IPAH patients.I diopathic pulmonary arterial hypertension (IPAH) is a fatal disease that causes right heart failure and death. The elevated pulmonary vascular resistance (PVR) and arterial pressure in IPAH patients result mainly from pulmonary vasoconstriction, vascular remodeling, and in situ thrombosis (1). A central aspect of pulmonary vascular remodeling is medial hypertrophy caused by sustained pulmonary vasoconstriction (2-4), excessive pulmonary artery smooth muscle cell (PASMC) proliferation (5), and inhibited PASMC apoptosis (6, 7), resulting in a narrowed vascular lumen and increased PVR. Although its etiology remains unclear, elevated levels of circulating mitogens, dysfunction or down-regulation of receptors and ion channels, upregulation of transporters, and heightened activity of elastases and glycoproteins have been implicated in IPAH (5,6,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) Transient receptor potential (TRP) channel genes may encode subunits that form receptor-(ROC) and store-(SOC) operated Ca 2ϩ channels in many cell types, including PASMC and pulmonary artery endothelial cells (PAEC) (28,(30)(31)(32)(33)(34). Ca 2ϩ entry through ROC and SOC increases [Ca 2ϩ ] cyt , allowing for phosphorylation of signal transduction proteins and transcription factors (23,24,(35)(36)(37)(38), that are essential for the progression of the cell cycle (21). High levels of [Ca 2ϩ ] cyt and sufficient levels of Ca 2ϩ in the SR are required for vascular smooth muscle cell proliferation (22,25,39). Because they regulate SR and cytoplasmic Ca 2ϩ , CCE and SOC may play significant roles in regulating cell proliferation (28,29). This study tested the hypothesis that canonical TRP (TRPC...

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“…In some studies, matrix metalloproteinases were found to contribute to the development of pulmonary arterial hypertension in animals but differences in the effects of matrix metalloproteinase inhibitors were observed between studies. Knowledge about matrix metalloproteinase/ tissue inhibitors of matrix metalloproteinase balance in humans with idiopathic pulmonary arterial hypertension is limited (25)(26)(27)(28)(29).…”

Section: Matrix Metalloproteinases and Tissue Inhibitors In Pulmonarymentioning

confidence: 99%

Circulating matrix metalloproteinases and tissue inhibitors of metalloproteinases levels in pediatric patients with congenital heart disease: Relationship to cardiac functions

Kılıç

Uçar²,

Özdemir³

et al. 2014

Anadolu Kardiyol Derg

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Objective: The pathological effects of matrix metalloproteinases and their tissue inhibitors in cardiovascular diseases are of considerable interest. In our study, we aimed to determine and evaluate the potential significance of circulating matrix metalloproteinases-2 and 9, tissue inhibitors of matrix metalloproteinases-1 and 2 levels in four patient subgroup of pediatric cardiology field and expose pathophysiologic differences between these groups. Methods: Eighty-seven patients with the diagnosis of congenital heart disease and 47 healthy controls were enrolled in the study. The study group was stratified to 4 subgroups; 14 patients with right ventricular volume overload, 30 patients with left ventricular volume overload, 19 patients with left to right shunt who developed pulmonary hypertension and 24 patients with cyanotic congenital heart disease. For evaluation of the relationships between serum matrix metalloproteinases and their tissue inhibitors levels with cardiac structures and functions; complete blood count, arterial oxygen saturation, detailed echocardiographic measurements (including tissue Doppler) in all patients and hemodynamic parameters of the patients who went to cardiac catheterization were recorded. Serum matrix metalloproteinase levels were determined by ELISA test. Statistical evaluations were performed with SPSS 16.0. For parameters showing normal distribution, comparisons were made with t-test and ANOVA test. However, for parameters without normal distribution, groups were compared with Mann-Whitney U test and KruskalWallis test. Results: We demonstrated that serum tissue inhibitors of matrix metalloproteinases-1 levels of patients with pulmonary hypertension secondary to congenital heart diseases were significantly higher than the patients with left to right shunt without pulmonary hypertension and controls (p<0.01). Although serum matrix metalloproteinases and their tissue inhibitors levels in patients with cyanotic congenital heart diseases and patients with right or left ventricular volume overload were found to be altered when compared with controls but not significant. Conclusion: Our data may suggest the possible role of matrix metalloproteinases and their tissue inhibitors on myocardial remodeling in congenital heart defects and especially in patients who developed pulmonary hypertension. (Anadolu Kardiyol Derg 2014; 14: 531-41)

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Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease

Cited by 262 publications

References 46 publications

Erythropoietin Upregulation in Pulmonary Arterial Hypertension

Erythropoietin Upregulation in Pulmonary Arterial Hypertension

Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension

Circulating matrix metalloproteinases and tissue inhibitors of metalloproteinases levels in pediatric patients with congenital heart disease: Relationship to cardiac functions

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