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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-2589
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 11 4635-4640
Copyright © 2006 by The Endocrine Society

Reductions of Circulating Matrix Metalloproteinase 2 and Vascular Endothelial Growth Factor Levels after Treatment with Pegvisomant in Subjects with Acromegaly

A. N. Paisley, C. J. O’Callaghan, K. C. Lewandowski, C. Parkinson, M. E. Roberts, W. M. Drake, J. P. Monson, P. J. Trainer and H. S. Randeva

Department of Endocrinology (A.N.P., M.E.R., P.J.T.), Christie Hospital, Manchester M20 4BX, United Kingdom; Department of Community Health and Epidemiology (C.J.O.), Queen’s University, Kingston, Ontario, Canada K7L 3N6; Department of Endocrinology and Metabolic Medicine (K.C.L.), The Medical University of Lodz, 90–419 Lodz, Poland; Department of Diabetes and Endocrinology (C.P.), The Ipswich Hospital, Ipswich IP4 5PD, United Kingdom; Department of Endocrinology (M.W.D., J.P.M.), St Bartholomew’s Hospital, London EC1A 7BE, United Kingdom; and Molecular Medicine Group (H.S.R.), Department of Biological Sciences, The University of Warwick, Coventry CV4 7AL, United Kingdom

Address all correspondence and requests for reprints to: Dr. Harpal S. Randeva, FRCP, Ph.D., Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, United Kingdom. E-mail: hrandeva{at}bio.warwick.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: Vascular endothelial growth factor (VEGF) is involved in activation of the matrix metalloproteinase (MMP) system; the latter is implicated in atherosclerosis and cardiovascular disease. Patients with acromegaly have reduced life expectancy primarily due to cardiac disease.

Aim: This study assessed plasma MMPs and VEGF levels in patients with active acromegaly (IGF-I > 130% upper limit of normal), and on treatment with pegvisomant.

Subjects and Methods: Twenty patients [nine female, mean age 56.1 ± 13.8 yr (mean ± SD)] were studied at baseline and on pegvisomant therapy and compared with data from 25 healthy volunteers (12 female; 56.6 ± 14.2 yr). Plasma MMP-2, MMP-9, and VEGF levels were measured.

Results: Serum IGF-I fell from a baseline (mean ± SD) level of 620.1 ± 209.3 ng/ml to 237.5 ± 118.5 ng/ml on pegvisomant (doses 10–60 mg; P < 0.001). MMP-2 levels at baseline were significantly higher in patients compared with healthy controls (380.7 ± 204.8 vs. 207.4 ± 62.6 ng/ml; P < 0.001), but with treatment a significant reduction in MMP-2 [380.7 ± 204.8 vs. 203.0 ± 77.4 ng/ml; P < 0.001] and VEGF (283.4 ± 233.6 vs. 229.1 ± 157.4 pg/ml; P = 0.008) was noted. There was no significant difference in MMP-9 levels between patients and controls at baseline (797.5 ± 142.1 vs. 788.3 ± 218.0 ng/ml; P = 0.87) or between baseline and posttreatment levels (797.5 ± 142.1 vs. 780.0 ± 214 ng/ml; P = 0.76).

Conclusions: Our novel data demonstrate that treatment of acromegaly with pegvisomant leads to reductions in MMP-2 and VEGF concentrations. Further studies are required to determine the significance of these findings with relation to cardiac disease.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ACROMEGALY IS ASSOCIATED with increased morbidity and mortality, with reduced life expectancy predominantly due to cardiac disease (1). The increase in cardiac disease is due to a combination of the various effects of elevated GH/IGF-I levels on the heart and vasculature and the increased prevalence of metabolic abnormalities including hypertension and diabetes mellitus (2). A specific cardiomyopathy exists in acromegaly characterized by biventricular concentric hypertrophy. This is due to a relative increase in myocyte size without enlargement of cardiac chambers and is present in over two thirds at diagnosis (3). Impaired diastolic and systolic function is seen with more long-standing disease (3); however, even in the presence of long-standing disease, encouraging studies have reported reversal of the cardiac structural and functional abnormalities with reduction of GH/IGF-I levels although not necessarily back to that of normal controls (3, 4, 5). Fewer studies have examined the vasculature, and it is uncertain whether there is accelerated atherosclerosis in these patients. Several studies have demonstrated an increased carotid artery intima-media thickness (6, 7) and endothelial dysfunction (8, 9) in patients with acromegaly, both of which are thought to be early features of atherosclerosis, but other reports, particularly that of Lie (10) refute this notion. In Lie’s review of 27 autopsies of patients with acromegaly, the prevalence of coronary artery disease was not increased.

Matrix metalloproteinases (MMPs), with over 20 identified, are a family of zinc-containing endoproteinases that remodel the extracellular matrix. Increased activity of MMPs, in particular the gelatinases (MMP-2 and MMP-9) (11), has been implicated in numerous disease processes, including atherosclerosis and cardiovascular disease (11, 12, 13, 14, 15, 16). MMP-2 (72 kDa) and MMP-9 (92 kDa) play a major role in acute myocardial ischemia and reperfusion injury (14) and vascular matrix remodeling (11). Peripheral concentrations of MMP-2 and MMP-9 are raised in patients with acute coronary syndromes (16), with increased expression and activation in human atherosclerotic plaques (12) and in cerebral ischemia (13). Studies suggest a role for MMP-2 and -9 in the pathology of plaque rupture. Consequently they are thought to be prognostic markers of ongoing inflammation and eventual plaque rupture (17). The expression and circulating levels of MMPs are up-regulated by a variety of factors (18), including vascular endothelial growth factor (VEGF) (19), which itself plays an important role in vasculogenesis, atherogenesis, and vascular remodeling.

Although glucose intolerance and hypertension are more prevalent in patients with acromegaly, some cardiovascular risk factors including total cholesterol (TC) and C-reactive protein levels are actually low in active disease (20). Treatment of acromegaly, either by surgery or medical therapy, returns many of these cardio-metabolic risk factors back to levels comparable with the normal population (21). Pegvisomant, a GH receptor antagonist, normalizes IGF-I levels in up to 97% of patients and can reverse some of the metabolic abnormalities encountered with acromegaly (20, 22, 23, 24, 25).

In acromegalic subjects, there are no data on circulating levels of the nontraditional cardiovascular risk factors, MMP-2 and -9 (11, 12, 13, 14, 15). Therefore, in the present study, we aimed to determine plasma levels of MMP-2, MMP-9, and VEGF, an endothelial cell-specific mitogen known to increase MMPs, in patients with active acromegaly, and moreover, we aimed to investigate the effect of pegvisomant therapy on their plasma concentrations.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Twenty patients with acromegaly (9 female, 11 male) and 25 healthy controls (12 female, 13 male) were included in the study (Table 1Go). Sixteen patients had undergone previous pituitary surgery (two twice), and 16 had received prior three-field external-beam pituitary radiotherapy. Some patients were on stable replacement with hydrocortisone (n = 7), T4 (n = 1), and sex steroids (n = 6) for the duration of the study. All patients had been diagnosed according to the current accepted criteria of a raised serum IGF-I with failure of GH suppression to less than 1 µg/liter after 75 g oral glucose (26). Patients were entered into a trial of pegvisomant therapy, having undergone a washout period from all other medication for their acromegaly (5 wk for dopamine agonists, 2 wk for sc octreotide; no patients on Sandostatin LAR or Lanreotide were recruited to this study). After the washout period, all subjects had a serum IGF-I level more than 1.3 times the upper limit of normal. After a loading dose of 80 mg, patients were commenced on a starting dose of 10 mg pegvisomant per day (sc injection), and this was titrated up by 5 mg every 8 wk until normal age-related serum IGF-I levels were attained. Patients’ responses to pegvisomant varied with time periods of up to 1 yr or more in some patients before biochemical remission was attained. This was reflected in the dose variation of pegvisomant: 10–60 mg/d.


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  		TABLE 1. Descriptive demographics contrasting controls and cases at baseline and univariate and multiple variable contrasts of covariates between baseline and posttreatment values for cases

 
Levels of MMP-2, MMP-9, and VEGF were measured in addition to TC, triglycerides (TG), serum glucose, and body mass index (BMI). All blood samples were taken in the fasting state at 0900 h at baseline before starting pegvisomant but after the washout period (IGF-I > 1.3 times upper limit of normal) and again once a normal serum IGF-I level had been attained (except in the case of two patients who failed to achieve normal IGF-I levels and, therefore, samples were taken at the point of the lowest IGF-I level). Controls were sampled at baseline to contrast with baseline assessments of patients and posttreatment values to determine any initial differences and/or return to "normal" values under treatment. The local research ethics committee approved the study, and written consent was obtained from each subject.

Assays

Serum IGF-I was measured using the Advantage method (Nichols Institute Diagnostics, San Juan Capistrano, CA) with intraassay and interassay coefficients of variation (CV) between 2 and 8%. Human MMP-2 (sensitivity 0.37 ng/ml; intraassay CV 6.3%) measurements were carried out with ELISA kits (Biotrak; Amersham Pharmacia Biotech, Little Chalfont, UK); and human VEGF (sensitivity < 9 pg/ml; intraassay CV 6.7%) and MMP-9 (total) (sensitivity 0.156 ng/ml; intraassay CV 2.9%) evaluations were performed using commercially available ELISA kits (Quantikine; R&D Systems, Minneapolis, MN) following the instructions.

Serum TC, TG, and glucose assays were measured using a Bayer ADVIA 1650 chemistry analyser (Bayer Diagnostics, Newbury, Berkshire, UK) by proprietary methods. The TC and TG methods, respectively, employ cholesterol oxidase and lipoprotein lipase/glycerol kinase. Glucose was determined using a glucose oxidase/linked peroxidase assay.

Statistical analysis

Simple descriptive statistics and tests of differences between patients and controls at baseline were assessed by means of generalized linear models using SAS version 8.2 software (SAS Institute Inc., Cary, NC). Univariate tests of differences between patients and controls were supplemented with multiple variable models controlling for age and gender. With respect to the assessment of changes over time within patients (baseline, posttreatment), nonindependence of repeated observations was accounted for in hierarchical linear models developed using MLwiN version 2.0 software (Institute of Education, London, UK). Essential modeling assumptions of random selection of patients (generalizability) and normality of error distributions, although not unreasonable, were not formally evaluated owing to sparse data. Single variable tests of differences between baseline and posttreatment observations and bivariate assessments of associations between each variable of interest and other covariates were supplemented with multiple variable models controlling for the potential effects of age and gender and other covariates as appropriate. Final model parameter estimates were derived from Markov-Chain Monte Carlo estimation using MLwiN default ("diffuse") priors. Statistical testing was by means of two-tailed assessments employing maximum likelihood methods. In all analyses, statistical significance was considered to be achieved when P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Results from 20 patients with acromegaly (nine female) with a mean age of 56.1 ± 13.8 yr and BMI (16 patients) of 31.1 ± 5.3 kg/m2 were compared with those from 25 healthy controls (12 female) with mean age of 56.6 ± 14.2 yr and BMI of 31.6 ± 5.2 kg/m2 (P = 0.91; P = 0.79, respectively). Descriptive demographics and contrasts of covariates between patients and controls at baseline and between baseline and posttreatment values within patients are presented in Table 1Go. At baseline, patients differed significantly from controls only with respect to their higher MMP-2 levels (P < 0.001). Levels of MMP-9 (P = 0.87), VEGF (P = 0.18), glucose (P = 0.52), TC (P = 0.16), and TG (P = 0.13) were all comparable between the two groups at baseline.

Serum IGF-I levels in the patient group fell from a baseline mean of 620.1 ng/ml (range 333–992) to 237.5 ng/ml (range 91–545; P < 0.001) after treatment with pegvisomant for a mean of 6.5 ± 5.5 months (range 1–16 months; Fig. 1Go). Patients’ responses to pegvisomant varied, as noted by the time periods, before biochemical remission was attained. Moreover, this was reflected in the doses of pegvisomant ranging from 10–60 mg daily (mean daily dose 18.25 mg). Similarly, posttreatment levels of MMP-2 (P < 0.001) and VEGF (P = 0.008) declined concurrently and significantly from baseline values, approaching the baseline values of the controls (P = 0.83, P = 0.65, respectively; Fig. 2Go), whereas levels of TC rose concomitantly (P < 0.001 vs. baseline), again approximating baseline control values (P = 0.87; Table 1Go). Levels of MMP-9 (P = 0.76), glucose (P = 0.70), and TG (P = 0.30) were unchanged under treatment.


Figure 1
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  		FIG. 1. Plot demonstrating fall in serum median IGF-I concentrations before and after therapy with pegvisomant (P < 0.001).

 

Figure 2
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  		FIG. 2. Mean ± SEM concentrations of MMP-2 and VEGF in normal individuals (control group) and in subjects with acromegaly before (Visit-1) and during pegvisomant therapy (Visit-2). a, P < 0.001 vs. control; b, P < 0.001 vs. Visit-1; c, P = 0.18 vs. control; d, P = 0.008 vs. Visit-1.

 
Although MMP-2 was statistically significantly positively associated with IGF-I (P = 0.002) and negatively with TC (P = 0.005) and TG (P = 0.015), none of these three achieved significance in a multiple variable model. However, Fig. 3Go depicts the relationship between MMP-2 and IGF-I levels over time, demonstrating that, in half of the patients, synchronous declines of greatest magnitude occurred in those with highest initial values. Similarly, although VEGF was statistically significantly positively associated with IGF-I (P = 0.027) and negatively with TC (P = 0.050) in univariate assessments, neither was significant in a model containing the other covariate. MMP-9 was not significantly associated with any other covariate tested. All tests of statistical significance in all models were unchanged when also controlling for age.


Figure 3
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  		FIG. 3. Plot of IGF-I vs. MMP-2 levels over time, where filled circles denote the baseline observation and open circles denote the observations after pegvisomant therapy, as linked sequentially by thin lines.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The gelatinase metalloproteinases (MMP-2 and MMP-9) are involved with both myocardial and vascular matrix remodeling under physiological and pathological conditions. The present study provides the first evidence that patients with active acromegaly, a patient group at increased risk of cardiac disease, have elevated MMP-2 levels that, like VEGF levels, normalize with pegvisomant therapy and are no longer different from control values. In addition, there was a statistically significant (positive) association between MMP-2 and IGF-I, and also VEGF and IGF-I. These findings are of interest in light of a previous study performed by Nagai et al. (27) who did not demonstrate any evidence of raised VEGF levels in patients with active acromegaly. The reduction in VEGF and consequently MMP-2 levels may partly be explained by the reduction in IGF-I levels, which is known to stimulate VEGF expression and, which, in turn, stimulates MMP activity (28). However, further studies are required to establish the preferential decline noted in MMP-2 and not MMP-9 in our study. Our findings add weight to the cardiovascular-risk profile benefits of pegvisomant therapy in adults with acromegaly, where studies have demonstrated a normalization of some cardiovascular risk factors (24).

Cardiac and vascular disease profile found in acromegaly is dominated more by cardiomyopathy than coronary atherosclerosis; for example, cardiac dysfunction with hypertrophy, dilatation, and diastolic filling abnormalities (3, 4, 5). Fewer studies have examined the vasculature, and it is uncertain whether there is accelerated atherosclerosis in these patients. However, others have reported that concomitant early arterial structural changes are also seen with Doppler examination confirming an increase in intima-media thickness in these patients (6, 9). There is currently much dispute as to whether the incidence of premature atherosclerosis is actually increased, with differing data reported (10, 29). Although the presence of atherosclerotic plaques has been reported in active acromegaly, it appears to be endothelial dysfunction that contributes most to the associated vascular morbidity (30). Limited data have suggested that impairment of flow-mediated dilatation, taken as a surrogate early marker for atherosclerosis, occurs with active disease and can be improved with treatment (8, 30). Our findings and the observations that MMPs are involved in the pathogenesis of cardiovascular disease (11, 12, 13, 14, 16, 17) are particularly interesting in the setting of acromegaly and its cardiovascular phenotype.

We have recently shown that GH replacement in GH-deficient subjects led to a more pronounced decline in MMP-9 compared with both MMP-2 and VEGF (31). Although IGF-I may provide an important contribution to MMP-2, -9, and VEGF levels, it is clear from our present study in patients with acromegaly and our previous observations in GH-deficient subjects (31) that IGF-I levels are not the only determinants of MMP and VEGF levels and, more importantly, the preferential decline in MMP-2 noted in the present study; a number of other factors and disease states influence MMPs and VEGF (14, 18, 32, 33). However, recent data demonstrate that raised IGF-I levels may be directly associated with increased mortality in subjects with treated acromegaly (34). Therefore, we speculate that pegvisomant-mediated reduction in IGF-I, with subsequent decrease in VEGF and MMP-2 concentrations could be at least one of the factors that might contribute to beneficial effects of pegvisomant therapy in modulating the cardiovascular risk in subjects with acromegaly.

In our present study, we did not demonstrate any significant effects on MMP-9 levels, but treatment with pegvisomant induced an impressive decline in MMP-2. The reason why MMP-9 levels remained unchanged is unclear. MMP-2 is predominantly synthesized in the mesenchymal cells, in particular the vascular smooth muscle cells. Vascular smooth muscle cell migration contributes to the development of vascular pathological states including intimal hyperplasia, which is a marker of endothelial dysfunction, a frequently encountered problem in patients with acromegaly. Therefore, the decrease in MMP-2/VEGF seen when acromegaly is effectively treated with pegvisomant could have beneficial effects in helping to improve the underlying endothelial dysfunction, although further studies will be necessary to confirm this. Although some studies have suggested that atherosclerosis is more prevalent in patients with acromegaly, there is no real convincing evidence, and it is thought that endothelial dysfunction is the predominant pathology that may contribute to the increased prevalence of hypertension and represent a risk factor for the cardiovascular complications seen in these patients (8).

In our current study, we were unable to correlate plasma levels of MMPs with size and invasiveness of tumor and also determine plasma levels of MMPs/VEGF in these acromegalic subjects in comparison to pituitary tumors of different histology. In vitro studies have shown that pituitary tumors/pituitary cells do indeed secrete MMPs and VEGF and regulate proliferation and hormone secretion in pituitary cells (35, 36, 37). Interestingly, as Turner et al. (38) report, assessment of MMP-2 expression in a cohort of human pituitary tumors showed no relationship with pituitary tumor behavior. Furthermore, MMP-9 expression was related to macroprolactinoma invasiveness and nonfunctioning tumor regrowth (37), suggesting that MMP-9 expression is related to aggressive tumor behavior. These observations are of interest, because in our cohort, MMP-2 levels were higher in acromegalics than controls, normalizing with treatment, but MMP-9 levels were no different in both groups. Furthermore, it is unclear whether GH hypersecretion is responsible for the increased MMP-2 and VEGF. In addition, whether the decrease in VEGF and MMP-2 levels seen is due to effective treatment of acromegaly or due to a specific action of pegvisomant therapy working directly at the GH receptor site remains to be elucidated. It would be interesting to see whether the findings with pegvisomant therapy also occur with somatostatin analogs and to conduct future studies designed to assess MMP and VEGF levels not only when normal IGF-I are achieved but also at intermediary time points during the treatment.

In summary, our study demonstrates unique data suggesting that treatment of active acromegaly with pegvisomant significantly lowers VEGF and MMP-2 levels. Finally, with the knowledge that VEGF and MMP-2 contribute to cardiac and endothelial dysfunction leading to cardiomyopathy and vascular disease such as hypertension, abnormalities commonly encountered in acromegaly, it follows that circulating levels should be kept as low as possible.


   Footnotes
 
This work was supported by P.J.T., through research grant support from Pfizer (1998–2006). The study was partially supported by a European Union grant (Centre of Excellence in Molecular Medicine QLK3-CT-2002-30326).

A.N.P., C.J.O., K.C.L., C.P., M.E.R., and H.S.R. have nothing to declare. W.M.D., J.P.M., and P.J.T. have previously consulted for and received lecture fees from Pfizer.

First Published Online August 22, 2006

Abbreviations: BMI, Body mass index; CV, coefficient of variation; MMP, matrix metalloproteinase; TC, total cholesterol; TG, triglyceride; VEGF, vascular endothelial growth factor.

Received November 30, 2005.

Accepted August 10, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ, Ibbertson HK 1994 Determinants of clinical outcome and survival in acromegaly. Clin Endocrinol (Oxf) 41:95–102[Medline]
  2. Colao A, Ferone D, Marzullo P, Lombardi G 2004 Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev 25:102–152[Abstract/Free Full Text]
  3. Colao A, Marzullo P, Di Somma C, Lombardi G 2001 Growth hormone and the heart. Clin Endocrinol (Oxf) 54:137–154[CrossRef][Medline]
  4. Vianna CB, Vieira ML, Mady C, Liberman B, Durazzo AE, Knoepfelmacher M, Salgado LR, Ramires JA 2002 Treatment of acromegaly improves myocardial abnormalities. Am Heart J 143:873–876[CrossRef][Medline]
  5. Colao A, Vitale G, Pivonello R, Ciccarelli A, Di Somma C, Lombardi G 2004 The heart: an end-organ of GH action. Eur J Endocrinol 151(Suppl 1):S93–S101
  6. Colao A, Spiezia S, Cerbone G, Pivonello R, Marzullo P, Ferone D, Di Somma C, Assanti AP, Lombardi G 2001 Increased arterial intima-media thickness by B-M mode echodoppler ultrasonography in acromegaly. Clin Endocrinol (Oxf) 54:515–524[CrossRef][Medline]
  7. Colao A, Marzullo P, Lombardi G 2002 Effect of a six-month treatment with lanreotide on cardiovascular risk factors and arterial intima-media thickness in patients with acromegaly. Eur J Endocrinol 146:303–309[Abstract]
  8. Maison P, Demolis P, Young J, Schaison G, Giudicelli JF, Chanson P 2000 Vascular reactivity in acromegalic patients: preliminary evidence for regional endothelial dysfunction and increased sympathetic vasoconstriction. Clin Endocrinol (Oxf) 53:445–451[CrossRef][Medline]
  9. Brevetti G, Marzullo P, Silvestro A, Pivonello R, Oliva G, Di Somma C, Lombardi G, Colao A 2002 Early vascular alterations in acromegaly. J Clin Endocrinol Metab 87:3174–3179[Abstract/Free Full Text]
  10. Lie JT 1980 Pathology of the heart in acromegaly: anatomic findings in 27 autopsied patients. Am Heart J 100:41–52[CrossRef][Medline]
  11. Creemers EE, Cleutjens JP, Smits JF, Daemen MJ 2001 Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure? Circ Res 89:201–210[Abstract/Free Full Text]
  12. Galis ZS, Sukhova GK, Lark MW, Libby P 1994 Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 94:2493–2503[Medline]
  13. Mun-Bryce S, Rosenberg GA 1998 Matrix metalloproteinases in cerebrovascular disease. J Cereb Blood Flow Metab 18:1163–1172[CrossRef][Medline]
  14. Wang W, Schulze CJ, Suarez-Pinzon WL, Dyck JR, Sawicki G, Schulz R 2002 Intracellular action of matrix metalloproteinase-2 accounts for acute myocardial ischemia and reperfusion injury. Circulation 106:1543–1549[Abstract/Free Full Text]
  15. Shah PK 2000 Plaque disruption and thrombosis: potential role of inflammation and infection. Cardiol Rev 8:31–39[CrossRef][Medline]
  16. Kai H, Ikeda H, Yasukawa H, Kai M, Seki Y, Kuwahara F, Yeno T, Sugi K, Imaizumi T 1998 Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol 32:368–372[Abstract/Free Full Text]
  17. Wainwright CL 2004 Matrix metalloproteinases, oxidative stress and the acute response to acute myocardial ischaemia and reperfusion. Curr Opin Pharmacol 4:132–138[CrossRef][Medline]
  18. Dollery CM, McEwan JR, Henney AM 1995 Matrix metalloproteinases and cardiovascular disease. Circ Res 77:863–868[Free Full Text]
  19. Wang H, Keiser JA 1998 Vascular endothelial growth factor upregulates the expression of matrix metalloproteinases in vascular smooth muscle cells: role of flt-1. Circ Res 83:832–840[Abstract/Free Full Text]
  20. Sesmilo G, Fairfield WP, Katznelson L, Pulaski K, Freda PU, Bonert V, Dimaraki E, Stavrou S, Vance ML, Hayden D, Klibanski A 2002 Cardiovascular risk factors in acromegaly before and after normalization of serum IGF-I levels with the GH antagonist pegvisomant. J Clin Endocrinol Metab 87:1692–1699[Abstract/Free Full Text]
  21. Jaffrain-Rea ML, Minniti G, Moroni C, Esposito V, Ferretti E, Santoro A, Infusino T, Tamburrano G, Cantore G, Cassone R 2003 Impact of successful transsphenoidal surgery on cardiovascular risk factors in acromegaly. Eur J Endocrinol 148:193–201[Abstract]
  22. Parkinson C, Drake WM, Wieringa G, Yates AP, Besser GM, Trainer PJ 2002 Serum lipoprotein changes following IGF-I normalization using a growth hormone receptor antagonist in acromegaly. Clin Endocrinol (Oxf) 56:303–311[CrossRef][Medline]
  23. Parkinson C, Kassem M, Heickendorff L, Flyvbjerg A, Trainer PJ 2003 Pegvisomant-induced serum insulin-like growth factor-I normalization in patients with acromegaly returns elevated markers of bone turnover to normal. J Clin Endocrinol Metab 88:5650–5655[Abstract/Free Full Text]
  24. Drake WM, Rowles SV, Roberts ME, Fode FK, Besser GM, Monson JP, Trainer PJ 2003 Insulin sensitivity and glucose tolerance improve in patients with acromegaly converted from depot octreotide to pegvisomant. Eur J Endocrinol 149:521–527[Abstract]
  25. Trainer PJ, Drake WM, Perry LA, Taylor NF, Besser GM, Monson JP 2001 Modulation of cortisol metabolism by the growth hormone receptor antagonist pegvisomant in patients with acromegaly. J Clin Endocrinol Metab 86:2989–2992[Abstract/Free Full Text]
  26. Trainer PJ 2002 Editorial: acromegaly—consensus, what consensus? J Clin Endocrinol Metab 87:3534–3536[Free Full Text]
  27. Nagai Y, Ando H, Nohara E, Yamashita H, Takamura T, Kobayashi K 2000 Plasma levels of vascular endothelial growth factor in patients with acromegaly. Horm Metab Res 32:326–329[Medline]
  28. Punglia RS, Lu M, Hsu J, Kuroki M, Tolentino MJ, Keough K, Levy AP, Levy NS, Goldberg MA, D’Amato RJ, Adamis AP 1997 Regulation of vascular endothelial growth factor expression by insulin-like growth factor I. Diabetes 46:1619–1626[Abstract]
  29. Vitale G, Pivonello R, Galderisi M, D’Errico A, Spinelli L, Lupoli G, Lombardi G, Colao A 2001 Cardiovascular complications in acromegaly: methods of assessment. Pituitary 4:251–257[CrossRef][Medline]
  30. Clayton RN 2003 Cardiovascular function in acromegaly. Endocr Rev 24:272–277[Abstract/Free Full Text]
  31. Randeva HS, Lewandowski KC, Komorowski J, Murray RD, O’Callaghan CJ, Hillhouse EW, Stepien H, Shalet SM 2004 Growth hormone replacement decreases plasma levels of matrix metalloproteinases (2 and 9) and vascular endothelial growth factor in growth hormone-deficient individuals. Circulation 109:2405–2410[Abstract/Free Full Text]
  32. Shweiki D, Itin A, Soffer D, Keshet E 1992 Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845[CrossRef][Medline]
  33. Kuroki M, Voest EE, Amano S, Beerepoot LV, Takashima S, Tolentino M, Kim RY, Rohan RM, Colby KA, Yeo KT, Adamis AP 1996 Reactive oxygen intermediates increase vascular endothelial growth factor expression in vitro and in vivo. J Clin Invest 98:1667–1675[Medline]
  34. Biermasz NR, Dekker FW, Pereira AM, van Thiel SW, Schutte PJ, van Dulken H, Romijn JA, Roelfsema F 2004 Determinants of survival in treated acromegaly in a single center: predictive value of serial insulin-like growth factor I measurements. J Clin Endocrinol Metab 89:2789–2796[Abstract/Free Full Text]
  35. Kawamoto H, Uozumi T, Kawamtot K, Arita K, Yano T, Hirohata T 1996 Type IV collagenase activity and cavernous sinus invasion in human pituitary adenomas. Acta Neurochir (Wien) 138:390–395[CrossRef][Medline]
  36. Pereda MP, Ledda MF, Goldberg V, Chervin A, Carrizo G, Molina H, Muller A, Renner U, Podhajcer OO, Arzt E, Stalla GK 2000 High levels of matrix metalloproteinases regulate proliferation and hormone secretion in pituitary cells. J Clin Endocrinol Metab 84:263–269
  37. Turner HE, Nagy ZS, Esiri MM, Harris AL, Wass JAH 2000 Role of matrix metalloproteinase 9 in pituitary tumors. J Clin Endocrinol Metab 85:2931–2935[Abstract/Free Full Text]
  38. Turner HE, Harris AL, Melmed S, Wass JAH 2003 Angiogenesis in endocrine tumors. Endocr Rev 24:600–632[Abstract/Free Full Text]




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