Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation. 2004;109:2405-2410
Published online before print May 3, 2004, doi: 10.1161/01.CIR.0000129763.51060.77
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
109/20/2405    most recent
01.CIR.0000129763.51060.77v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Randeva, H. S.
Right arrow Articles by Shalet, S. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Randeva, H. S.
Right arrow Articles by Shalet, S. M.
Related Collections
Right arrow Acute coronary syndromes
Right arrow Chronic ischemic heart disease
Right arrow Secondary prevention
Right arrow Mechanism of atherosclerosis/growth factors
Right arrow Pathophysiology

(Circulation. 2004;109:2405-2410.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Growth Hormone Replacement Decreases Plasma Levels of Matrix Metalloproteinases (2 and 9) and Vascular Endothelial Growth Factor in Growth Hormone–Deficient Individuals

Harpal S. Randeva, PhD, FRCP; Krzysztof C. Lewandowski, MD, MRCP; Jan Komorowski, PhD; Robert D. Murray, MRCP; Chris J. O’Callaghan, PhD; Edward W. Hillhouse, PhD, FRCP; Henryk Stepien, PhD; Stephen M. Shalet, MD, FRCP

From the Molecular Medicine Research Group, Biological Sciences, University of Warwick, UK (H.S.R., K.C.L., E.W.H.); the Department of Endocrinology, The Medical University of Lodz, Poland (J.K., H.S.); the Department of Endocrinology, Christie Hospital, Manchester, UK (R.D.M., S.M.S.); and the Department of Community Health and Epidemiology, Queen’s University, Kingston, Ontario, Canada (C.J.O.).

Correspondence to Dr Harpal S. Randeva, Molecular Medicine Research Group, Department of Biological Sciences, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK. E-mail hrandeva{at}bio.warwick.ac.uk

Received February 4, 2004; revision received February 20, 2004; accepted February 23, 2004.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background— Matrix metalloproteinases (MMP) are implicated in cardiovascular disease. Growth hormone (GH) deficiency is associated with increased cardiovascular mortality. We assessed whether GH replacement, in GH-deficient adults, has any effect on plasma levels of MMP-2 and MMP-9 and on vascular endothelial growth factor (VEGF), known to activate MMPs.

Methods and Results— The study comprised 66 GH-deficient adults, 37.8±14.7 years of age (37 female). Plasma MMP-2 and MMP-9, VEGF, and insulin-like growth factor-1 (IGF-1) were measured at baseline (V1), at 12 months (V2), and at 24 months of GH treatment (V3). IGF-1 levels rose under GH replacement (mean±SD): V1, 151.6±91.9 µg/mL; V2, 270.2±114.8 µg/mL; and V3, 266.2±109.8 (V1 versus V2; P<0.001: V2 versus V3; P=0.76). MMP-9 exhibited the most pronounced and sustained decline from 1248.0±651.1 ng/mL at V1, 949.2±457.7 ng/mL at V2, and 760.8±386.1 ng/mL at V3 (P<0.001 at all time points). A similar pattern was detected for VEGF levels: 358.5±209.0 pg/mL at V1, 310.6±225.7 pg/mL at V2 (P<0.001), and 283.7±202.7 pg/mL at V3 (V2 versus V3; P=0.005). MMP-2 demonstrated a significant decline initially from V1 to V2 (1134.4±217.8 ng/mL versus 1074.5±203.0 ng/mL, respectively; P=0.031), reaching a plateau at V3 (1072.3±220.2 ng/mL) (V2 versus V3; P=0.93). A negative relation existed between MMP-9 versus IGF-1 and MMP-2 versus IGF-1 (P<0.001 and P=0.007, respectively) as well as between VEGF and IGF-1 (P<0.001).

Conclusions— These changes in MMPs and VEGF may contribute to the anticipated reduction in vascular mortality in hypopituitary adults receiving GH replacement.


Key Words: atherosclerosis • cardiovascular diseases • growth substances • metalloproteinases • vasculature


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Cardiovascular disease is a recognized cause of premature mortality in hypopituitary patients1 in whom all pituitary hormone deficits are replaced except for growth hormones (GH). GH mediates many of its anabolic action through liver-derived insulin-like growth factor-1 (IGF-1). Growth hormone–deficient (GHD) adults, characterized by low or low-normal IGF-1 levels, also have impaired cardiac structure and performance, endothelial dysfunction, and vascular disease with increased intima-media thickness and premature atherosclerosis.2–5 GH plays an important role, not only in modulating metabolic factors and endothelial function but also in myocardial and vascular remodeling.

Matrix metalloproteinases (MMPs) are proteolytic enzymes that normally remodel the extracellular matrix and pathologically attack substrates as part of an inflammatory response. Increased activity of MMPs has been implicated in numerous disease processes, including atherosclerosis and cardiovascular disease.6,7–12 The major MMP species in the myocardium and vasculature are the gelatinases (MMPs 2 and 9), MMP-1 (interstitial collagenase), and Mt1-MMP. MMP-2 (72-kDa) and MMP-9 (92-kDa) play a major role in acute myocardial ischemia and reperfusion injury9 and vascular matrix remodeling.10 Furthermore, increased expression of MMP-9 has been demonstrated in the vulnerable regions of human atherosclerotic plaques;7 increased matrix degradation by MMPs has been implicated as one of the key factors that leads to plaque instability.11 Peripheral concentrations of MMP-2 and MMP-9 are reported to be raised in patients with acute coronary syndromes,12 with increased expression and activation of MMP-2 and MMP-9 noted in cerebral ischemia.8

Chronic subclinical inflammation plays a role in the pathogenesis of atherosclerosis,13 and both C-reactive protein (CRP) and interleukin-6 (IL-6), markers of subclinical inflammation, are independent predictors of cardiovascular disease (CVD) risk.14,15 In addition to proinflammatory states, expression of MMPs is upregulated by a variety of hormones and growth factors, including vascular endothelial growth factor (VEGF).16 VEGF, a homodimeric glycoprotein, plays an important role in vasculogenesis, atherogenesis, and vascular remodeling in response to "injury."17,18 VEGF, stimulated by hypoxia,17 upregulates the expression of matrix metalloproteinases.16

GH replacement in adults, in the setting of hypopituitarism, leads to an improvement in metabolic and cardiovascular risk profile19–21; in addition, the premature atherosclerosis and endothelial dysfunction, noted in these individuals, improves with GH treatment.4,5 Thus, GH replacement modulates metabolic, endothelial, and vascular function; therefore, in the present study, we aimed to investigate the effects of GH replacement, in GH-deficient adults, on plasma concentrations of MMP-2, MMP-9, and VEGF.


*    Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Patients
The study cohort comprised 66 GHD adults (29 men, 37 women), mean age of 37.8±14.7 years, with a mean body mass index (BMI) of 29.6±7.7 kg/m2. All patients with isolated GH deficiency underwent two provocative tests. All but 7 of the patients were subject to insulin-induced hypoglycemia. Arginine and glucagon stimulation tests were used if the insulin-induced hypoglycemia was contraindicated. Using conventional guidelines, a peak GH response of <9 mU/L was regarded as GH deficiency. Twenty-two patients had isolated GH deficiency, and the remaining 44 had varying degrees of hypopituitarism. The latter patients were receiving stable replacement with corticosteroids, thyroxine, and sex steroids for the duration of the study. In the female cohort, 19 patients were gonadotrophin-deficient, 16 of whom were receiving estrogen replacement. None of the patients was taking lipid-lowering therapy. The primary pathological diagnoses were pituitary adenoma (n=22), craniopharyngioma (n=9), idiopathic GH deficiency (n=4), histiocytosis X (n=2), empty sella syndrome (n=1), pituitary apoplexy (n=1), and radiation-induced GH deficiency resulting from successful treatment of malignant brain tumor or acute lymphoblastic leukemia (n=27). In addition, after informed consent, 116 healthy volunteers (48 men, 68 women) with a mean age of 35.9±16.6 years and a BMI of 28.9±8.2 kg/m2 were recruited from the medical school and hospital, to act as the control population.

Study Protocol
The design of the study was an open treatment trial of GH replacement over a 2-year period. Before commencing GH replacement, patients underwent physical examination and blood was drawn for the measurement of IGF-1, matrix metalloproteinase 2 (MMP-2), MMP-9, and VEGF. The patients were taught to self-inject GH by using an automated pen device (Genotropin Pen, Pharmacia and Upjohn), and when competent were commenced on GH at a dose of 0.27 mg/d. The GH dose was subsequently adjusted at intervals of 4 to 6 weeks to normalize the serum IGF-1 within the range of +2 to –2 SD of the age-adjusted mean in the absence of GH-related side effects. After an overnight fast, plasma samples were stored for the measurements of IGF-1, MMP-2, MMP-9, and VEGF, after 12 and 24 months of GH treatment. In addition, BMI and waist-to-hip ratio (WHR) were documented. Ethical approval for this study was granted by the South Manchester Local Research Ethics Committee, and written consent was obtained from each subject.

Assays
Serum samples were analyzed for IGF-1 by means of a radioimmunoassay, after separation of IGFs from IGF-1–binding proteins (IGFBPs) by acid/alcohol extraction. Des(1–3)-IGF-1 was used as radioligand to minimize interference of IGBPs in the extract. The intra-assay and interassay coefficients of variation (CV) were 10% and 3.1%, respectively.

Human VEGF (sensitivity, <9 pg/mL; intra-assay precision [CV], 6.7%) and MMP-9 (total) (sensitivity, 0.156 ng/mL; CV, 2.9%) evaluations were performed with the use of ELISA kits (Quantikine, R & D Systems). Human MMP-2 (sensitivity, 0.37 ng/mL; CV, 6.3%) measurements were carried out with ELISA kits (Biotrak, Amersham Pharmacia Biotech). Serum levels of CRP and IL-6 were measured by ELISA (Diagnostic Systems Laboratory Inc and R & D Systems, respectively), with an interassay CV of 6.4% for CRP and 5.9% for IL-6.

Statistical Analysis
The data were analyzed by means of generalized linear mixed (fixed and random effect) hierarchical (patient and observation) statistical models with a single patient-level random effect parameter, such that total observed variation could be apportioned to that occurring between patients versus within a patient. Models were generated with the use of MLwiN software (Institute of Education, London, UK), and the significance of model parameters was assessed by maximum likelihood methods with 2-tailed tests. Simple descriptive statistics and crude Pearson correlation coefficients were derived by means of SAS v 8.0 software (SAS Institute Inc). In all analyses, statistical significance was considered achieved for a value of P<0.05.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
down arrowDiscussion
 down arrowReferences
 
Table 1 illustrates the changes over time of the covariates of interest. IGF-1 levels rose in response to GH replacement by 12 months (P<0.001), a significant increase that was maintained but not altered (P=0.76) after 24 months of observation (P<0.001). Concomitant declines were observed in MMP-2, MMP-9, and VEGF levels. Of these, MMP-9 exhibited the most pronounced and sustained decline from a mean baseline level of 1248.0±651.1 ng/mL through 949.2±457.7 ng/mL at 12 months to 760.8±386.1 ng/mL by 24 months of observation. At each observation, the decline in MMP-9 levels from the previous observation was statistically significant (P<0.001 for both). A similar pattern of continued decline over the total period of observation was detected for VEGF levels (Table 1), with the 12-month observations significantly less than baseline (P<0.001) and 24-month levels significantly less than at 12 months (P=0.005). MMP-2, CRP, and IL-6 all demonstrated an initial significant decline from baseline to 12 months (P=0.031; P<0.001, and P<0.001, respectively), which subsequently reached a plateau, such that the 24-month observations did not differ significantly from the levels observed at 12 months (P=0.93, P=0.42, and P=0.49, respectively).


View this table:
[in this window]
[in a new window]
  		TABLE 1. Descriptive Statistics After Growth Hormone Replacement Over Time

Associations between IGF-1 levels and other covariates of interest, as quantified by hierarchical models and simple Pearson correlations, are presented in Table 2. With respect to the MMP under consideration, whereas the overall negative relations with IGF-1 (Figure 1, A and B) are each statistically significant (MMP-9, P<0.001, and MMP-2, P=0.007, respectively), the absolute magnitude of the negative relation between IGF-1 and MMP-9 is greater than that observed for MMP-2 (–2.140 versus –0.356, respectively). This relative strength of association is also reflected in the corresponding significant correlations observed between changes in MMP-9 and IGF-1 values from baseline to 12 and 24 months of observation, which were not present in the case of MMP-2. Similarly, the overall statistically significant negative relation observed between VEGF and IGF-1 levels (–0.342, P<0.001; Figure 1C) demonstrated somewhat weaker correlations between actual changes in values over time of the study. Furthermore, there were overall statistically significant negative relations observed between IGF-1 levels and CRP and IL-6, respectively (–69.81, P<0.001 and –125.73, P<0.001); the relative strengths of these relations with IGF-1 are demonstrated by the corresponding correlations between actual changes in values over time of the study (Table 2).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Parameter Estimates, Standard Errors, and P Values From Univariate Two-Level Generalized Linear Mixed Models of IGF-1 (µg/mL) and Corresponding Pearson Correlation Coefficients From Nonhierarchical Analysis



View larger version (29K):
[in this window]
[in a new window]
  		Figure 1. Plot of MMP-9 (A), MMP-2 (B), and VEGF (C) versus IGF-1 levels over time, where • denotes the baseline observation and {circ} denotes 12-month and 24-month observations as linked sequentially by thin lines. Bold line depicts overall best-fit linear relation as determined by a hierarchical mixed linear model.

It is of interest to note that the effects of GH replacement were also observed with respect to a consistently declining waist circumference and WHR but a virtually unchanged BMI. Indeed, hierarchical analysis of the data found no significant correlation between BMI and the covariates MMP-2 ({chi}21df=0.04; P=0.84), MMP-9 ({chi}21df=1.78; P=0.18), and VEGF ({chi}21df=3.50; P=0.061). In contrast, both MMP-9 and VEGF demonstrated positive associations with WHR ({chi}21df=16.97 and {chi}21df=17.42, respectively; P<0.001 for both); however, MMP-2 did not demonstrate positive associations ({chi}21df=0.27; P=0.60). A positive and statistically significant relation between MMP-2 and MMP-9 was observed ({chi}21df=7.44; P=0.006), but not between MMP-2 and VEGF ({chi}21df=0.80; P=0.37). Unlike MMP-2, MMP-9 levels were strongly and positively associated with VEGF ({chi}21df=43.85; P<0.001). Both MMP-9 and VEGF were positively related to age ({chi}21df=6.14; P=0.013: {chi}21df=5.28; P=0.022), the relation persisting even after accounting for the changes over time of the study. No apparent relation between MMP-2 and age was seen ({chi}21df=1.49; P=0.22). From nonhierarchical analysis, associations between covariates measured are quantified by simple Pearson correlation coefficients at baseline and also for changes in measured covariates from baseline at 24 months (Table 3) of GH replacement.


View this table:
[in this window]
[in a new window]
  		TABLE 3. Pearson Correlation Coefficients Between Covariates of Interest at Baseline and Between Changes in Covariates of Interest Where Change Values Are Calculated From Baseline (V1) to 24 Months (V2) of Observation

There were no statistically significant differences in age (35.9±16.6 versus 37.8±14.7 years; P=0.30) or BMI (28.9±8.2 kg/m2 versus all time points; P=0.60, P=0.82, P=0.74) between the control group compared with GHD subjects, respectively. Control subjects, compared with GHD subjects, had significantly lower CRP (2.86±1.1 versus 4.49±1.61 mg/L; P<0.001) and IL-6 (1.55±0.68 versus 2.39±1.24 pg/mL; P<0.001) levels at baseline; however, no significant differences were detected between the CRP and IL-6 values of control subjects and those of GHD subjects at 12 months (CRP, P=0.25; IL-6, P=0.21) and 24 months (CRP, P=0.40; IL-6, P=0.48) of GH replacement. Likewise, at baseline, MMP-9 levels (730±310 versus 1248±651.1 ng/mL; P<0.001), MMP-2 (860±190 versus 1134.4±217.8 ng/mL; P<0.001) levels, and VEGF levels (276±180 versus 358.5±209 ng/mL; P<0.001) were lower in control subjects compared with GHD subjects. As noted, with GH replacement, MMP-9, MMP-2, and VEGF decreased, but GHD subjects still maintained significantly higher levels of these variables after 12 months of GH replacement compared with control subjects (Figure 2). However, at 24 months of GH replacement, there were no significant differences noted in MMP-9 and VEGF levels between the two groups, but MMP-2 levels remained significantly higher in GHD subjects (P<0.01; Figure 2).



View larger version (30K):
[in this window]
[in a new window]
  		Figure 2. Mean±SEM concentrations of MMP-9 (A), MMP-2 (B), and VEGF (C) in normal individuals (control group) and in GHD subjects before (baseline) and during GH replacement, at 12 and 24 months.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The present study provides the first evidence that GH replacement decreases plasma concentrations of MMP-2, MMP-9, and VEGF in GHD adults, a patient group at increased risk of CVD. Of these MMPs, which are known to be implicated in CVD and cerebrovascular disease,7–12,22,23 the decline in MMP-9 was much greater. In addition, there was a statistically significant (negative) association between VEGF and IGF-1 and the MMPs and IGF-1, particularly MMP-9. Of note, the levels of MMP-9 and VEGF were not significantly different from those of the control population at 24 months of GH replacement, although MMP-2 levels remained higher (P<0.01) in GHD subjects. Our findings add weight to the cardiovascular risk profile benefits of GH replacement in GHD adults.4,19,20

GHD adults as a group are prone to abnormal cardiac structure and function and premature atherosclerosis, all of which improve with GH treatment.3,5,19 The fall in plasma MMPs after GH replacement noted in this study is therefore of interest, given that both MMP-2 and MMP-9 remodel cardiac and vascular extracellular matrix under physiological and pathological conditions. MMP-9 has been shown to impair cardiac contraction and depress systolic function,24 a phenotype seen in GHD subjects.3,19 Furthermore, MMP-9 activity has been observed in unstable carotid plaques, with corresponding increased plasma MMP-9 (but not MMP-2) concentrations22; MMP-9 has been implicated in plaque rupture.23 Our findings are therefore interesting, given that a relative increase in the incidence of cerebrovascular disease is reported to be even more marked than the increase in cardiac disease in subjects with hypopituitarism.25

Low or low normal IGF-1 levels, as seen in GHD individuals, may play a role in the pathogenesis of ischemic heart disease.4,20 Moreover, an independent association between IGF-1 and risk of ischemic heart disease has been described in a recent population-based, case-control study.26 Our data may provide a plausible link between IGF-1 change and the pathogenesis of increased vascular disease associated with GHD. GH replacement led to a rise in IGF-1 and a simultaneous decline in MMPs and VEGF; significant negative correlations were noted between IGF-1 and MMPs and between IGF-1 and VEGF, the magnitude of the correlation being greatest with MMP-9.

How does GH lead to the observed fall in plasma MMPs and VEGF? Despite the significant negative correlation between VEGF and IGF-1 and between MMPs and IGF-1 noted by us, it remains to be elucidated whether GH effects on MMPs and VEGF represent a direct GH or IGF-1 effect, or indeed both. Furthermore, in vitro data provide conflicting evidence on the effects of IGF-1 on MMPs, with some studies showing a stimulatory effect of IGF-1 on MMP-2 and MMP-9,27 whereas others demonstrated an inhibitory effect of IGF-1 on these MMPs.28–30 With regard to VEGF, there are data that show IGF-1 to enhance VEGF gene expression.31 However, Nagai et al,32 despite raised IGF-1 levels, failed to note any significant increase in plasma VEGF concentrations in acromegalic subjects. These conflicting findings, in our opinion, raise the possibility that the potential effects of GH/IGF-1 on the MMP system and VEGF may vary, depending on the target tissue. Also, given that the relation between GH status, IGF-I levels, and IGF-binding proteins varies in different physiological and pathological states, extrapolation from our data to other disease entities needs to be cautious.

MMP-2 is synthesized predominantly by mesenchymal cells (smooth muscle and fibroblasts). On the other hand, endothelial cells, macrophages, and infiltrating inflammatory cells are the predominant source of MMP-9. Many factors stimulate the production of these MMPs, including oxidant stress and inflammatory cytokines.11 Individuals with GH deficiency have enhanced oxidative stress and elevated inflammatory markers, including cytokines,21 which decrease with GH therapy, as noted in the present study and by others.21 Furthermore, we observed MMP-9 to correlate positively with CRP and IL-6, a finding demonstrated by others in subjects with diabetes.33 It is likely, therefore, that the fall in MMPs observed may in part be secondary to the reduced proinflammatory milieu.

VEGF, shown to upregulate MMPs, is produced by endothelial cells in response to vascular "injury."17,18 The decline of plasma VEGF concentrations may be potentially significant in view of recent observations suggesting that VEGF upregulates the expression of cyclooxygenase-2 in human endothelial cells, leading to increased synthesis of proinflammatory prostaglandins.34 Like MMPs, a positive correlation was noted between VEGF and CRP/IL-6. In GHD adults, the improvement in vasculature and endothelial function with GH replacement4 may therefore also be related to the fall in VEGF.

Adipose tissue, one of the main targets of GH/IGF-1, is an independent risk factor for CVD. We observed a significant decline in waist circumference (WC) and WHR with GH therapy. More importantly, the concentrations of VEGF and MMP-9 were significantly (positively) associated with WC and WHR, both WC and WHR being recognized as better predictors of CVD than BMI. Our findings are intriguing, given that human adipocytes produce and secrete MMP-2 and MMP-9 (and VEGF), all being involved in adipose tissue differentiation35 and development.36 Hence, the fall in MMPs and VEGF seen may also be explained by the reduction in abdominal fat. In addition, the greater fall in MMP-9 raises the possibility of a differential effect of GH/IGF-1 on MMPs, either direct or indirect, similar to that seen with the adipocytokine, leptin.37

In conclusion, we present novel findings that GH decreases concentrations of VEGF and MMP-9, and, to a lesser extent, MMP-2 in GHD adults. Although the exact clinical significance of our findings remain to be fully elucidated, we postulate that our observations may be important in the context of the role of MMPs in CVD and cerebrovascular disease, from which GHD adults are at increased risk. The possibility that a reduction in MMPs and VEGF seen with GH reflect a reduction in overall CVD risk need to be tested in clinical, controlled studies.


*    Acknowledgments
 
This work was supported in part by an educational grant from Pharmacia and an EU grant QLK3-CT-2002–30326.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Rosen T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet. 1990; 336: 285–288.[CrossRef][Medline] [Order article via Infotrieve]
  2. Rosen T, Eden S, Larson G, et al. Cardiovascular risk factors in adult patients with growth hormone deficiency. Acta Endocrinol (Copenh). 1993; 129: 195–200.[Medline] [Order article via Infotrieve]
  3. Colao A, Marzullo P, Di Somma C, et al. Growth hormone and the heart. Clin Endocrinol (Oxf). 2001; 54: 137–154.[CrossRef][Medline] [Order article via Infotrieve]
  4. Evans LM, Davies JS, Goodfellow J, et al. Endothelial dysfunction in hypopituitary adults with growth hormone deficiency. Clin Endocrinol (Oxf). 1999; 50: 457–464.[CrossRef][Medline] [Order article via Infotrieve]
  5. Pfeifer M, Verhovec R, Zizek B, et al. Growth hormone (GH) treatment reverses early atherosclerotic changes in GH-deficient adults. J Clin Endocrinol Metab. 1999; 84: 453–457.[Abstract/Free Full Text]
  6. Komorowski J, Pasieka Z, Jankiewicz-Wika J, et al. Matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases and angiogenic cytokines in peripheral blood of patients with thyroid cancer. Thyroid. 2002; 12: 655–662.[CrossRef][Medline] [Order article via Infotrieve]
  7. Galis ZS, Sukhova GK, Lark MW, et al. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994; 94: 2493–2503.[Medline] [Order article via Infotrieve]
  8. Mun-Bryce S, Rosenberg GA. Matrix metalloproteinases in cerebrovascular disease. J Cereb Blood Flow Metab. 1998; 18: 1163–1172.[CrossRef][Medline] [Order article via Infotrieve]
  9. Wang W, Schulze CJ, Suarez-Pinzon WL, et al. Intracellular action of matrix metalloproteinase-2 accounts for acute myocardial ischemia and reperfusion injury. Circulation. 2002; 106: 1543–1549.[Abstract/Free Full Text]
  10. Creemers EE, Cleutjens JP, Smits JF, et al. Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure? Circ Res. 2001; 89: 201–210.[Abstract/Free Full Text]
  11. Shah PK. Plaque disruption and thrombosis: potential role of inflammation and infection. Cardiol Rev. 2000; 8: 31–39.[CrossRef][Medline] [Order article via Infotrieve]
  12. Kai H, Ikeda H, Yasukawa H, et al. Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol. 1998; 32: 368–372.[Abstract/Free Full Text]
  13. Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med. 1999; 340: 115–126.[Free Full Text]
  14. Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000; 342: 836–843.[Abstract/Free Full Text]
  15. Ridker PM, Rifai N, Stampfer MJ, et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000; 101: 1767–1772.[Abstract/Free Full Text]
  16. Wang H, Keiser JA. Vascular endothelial growth factor upregulates the expression of matrix metalloproteinases in vascular smooth muscle cells: role of flt-1. Circ Res. 1998; 83: 832–840.[Abstract/Free Full Text]
  17. Shweiki D, Itin A, Soffer D, et al. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992; 359: 843–845.[CrossRef][Medline] [Order article via Infotrieve]
  18. Kuroki M, Voest EE, Amano S, et al. Reactive oxygen intermediates increase vascular endothelial growth factor expression in vitro and in vivo. J Clin Invest. 1996; 98: 1667–1675.[Medline] [Order article via Infotrieve]
  19. Colao A, di Somma C, Cuocolo A, et al. Improved cardiovascular risk factors and cardiac performance after 12 months of growth hormone (GH) replacement in young adult patients with GH deficiency. J Clin Endocrinol Metab. 2001; 86: 1874–1881.[Abstract/Free Full Text]
  20. Murray RD, Wieringa GE, Lissett CA, et al. Low-dose GH replacement improves the adverse lipid profile associated with the adult GH deficiency syndrome. Clin Endocrinol (Oxf). 2002; 56: 525–532.[CrossRef][Medline] [Order article via Infotrieve]
  21. Sesmilo G, Biller BM, Llevadot J, et al. Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency: a randomized, controlled clinical trial. Ann Intern Med. 2000; 133: 111–122.[Abstract/Free Full Text]
  22. Loftus IM, Naylor AR, Goodall S, et al. Increased matrix metalloproteinase-9 activity in unstable carotid plaques: a potential role in acute plaque disruption. Stroke. 2000; 31: 40–47.[Abstract/Free Full Text]
  23. Loftus IM, Naylor AR, Bell PR, et al. Plasma MMP-9 - a marker of carotid plaque instability. Eur J Vasc Endovasc Surg. 2001; 21: 17–21.[CrossRef][Medline] [Order article via Infotrieve]
  24. Rouet-Benzineb P, Buhler JM, Dreyfus P, et al. Altered balance between matrix gelatinases (MMP-2 and MMP-9) and their tissue inhibitors in human dilated cardiomyopathy: potential role of MMP-9 in myosin-heavy chain degradation. Eur J Heart Fail. 1999; 1: 337–352.[CrossRef][Medline] [Order article via Infotrieve]
  25. Tomlinson JW, Holden N, Hills RK, et al. Association between premature mortality and hypopituitarism: West Midlands Prospective Hypopituitary Study Group. Lancet. 2001; 357: 425–431.[CrossRef][Medline] [Order article via Infotrieve]
  26. Juul A, Scheike T, Davidsen M, et al. Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation. 2002; 106: 939–944.[Abstract/Free Full Text]
  27. Anne-Valerie R, Christelle D, Yannick F, et al. Human growth hormone stimulates proteinase activities of rabbit bone cells via IGF-I. Biochem Biophys Res Commun. 2000; 268: 875–881.[CrossRef][Medline] [Order article via Infotrieve]
  28. Wilson MJ, Sellers RG, Wiehr C, et al. Expression of matrix metalloproteinase-2 and -9 and their inhibitors, tissue inhibitor of metalloproteinase-1 and -2, in primary cultures of human prostatic stromal and epithelial cells. J Cell Physiol. 2002; 191: 208–216.[CrossRef][Medline] [Order article via Infotrieve]
  29. Lupia E, Elliot SJ, Lenz O, et al. IGF-1 decreases collagen degradation in diabetic NOD mesangial cells: implications for diabetic nephropathy. Diabetes. 1999; 48: 1638–1644.[Abstract]
  30. Pattison ST, Melrose J, Ghosh P, et al. Regulation of gelatinase-A (MMP-2) production by ovine intervertebral disc nucleus pulposus cells grown in alginate bead culture by transforming growth factor-beta(1) and insulin like growth factor-I. Cell Biol Int. 2001; 25: 679–689.[CrossRef][Medline] [Order article via Infotrieve]
  31. Punglia RS, Lu M, Hsu J, et al. Regulation of vascular endothelial growth factor expression by insulin-like growth factor I. Diabetes. 1997; 46: 1619–1626.[Abstract]
  32. Nagai Y, Ando H, Nohara E, et al. Plasma levels of vascular endothelial growth factor in patients with acromegaly. Horm Metab Res. 2000; 32: 326–329.[Medline] [Order article via Infotrieve]
  33. Haffner SM, Greenberg AS, Weston WM, et al. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation. 2002; 106: 679–684.[Abstract/Free Full Text]
  34. Tamura M, Sebastian S, Gurates B, et al. Vascular endothelial growth factor up-regulates cyclooxygenase-2 expression in human endothelial cells. J Clin Endocrinol Metab. 2002; 87: 3504–3507.[Abstract/Free Full Text]
  35. Bouloumie A, Sengenes C, Portolan G, et al. Adipocyte produces matrix metalloproteinases 2 and 9: involvement in adipose differentiation. Diabetes. 2001; 50: 2080–2086.[Abstract/Free Full Text]
  36. Lijnen HR, Maquoi E, Hansen LB, et al. Matrix metalloproteinase inhibition impairs adipose tissue development in mice. Arterioscler Thromb Vasc Biol. 2002; 22: 374–379.[Abstract/Free Full Text]
  37. Randeva HS, Murray RD, Lewandowski KC, et al. Differential effects of GH replacement on the components of the leptin system in GH-deficient individuals. J Clin Endocrinol Metab. 2002; 87: 798–804.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Clin. Endocrinol. Metab.Home page
C. Franco, B. Andersson, L. Lonn, B.-A. Bengtsson, J. Svensson, and G. Johannsson
Growth Hormone Reduces Inflammation in Postmenopausal Women with Abdominal Obesity: A 12-Month, Randomized, Placebo-Controlled Trial
J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2644 - 2647.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
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
Reductions of Circulating Matrix Metalloproteinase 2 and Vascular Endothelial Growth Factor Levels after Treatment with Pegvisomant in Subjects with Acromegaly
J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4635 - 4640.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
E. R Christ, M. H Cummings, M. Stolinski, N. Jackson, P. J Lumb, A. S Wierzbicki, P. H Sonksen, D. L Russell-Jones, and A M. Umpleby
Low-density lipoprotein apolipoprotein B100 turnover in hypopituitary patients with GH deficiency: a stable isotope study.
Eur. J. Endocrinol., March 1, 2006; 154(3): 459 - 466.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. Colao, C. Di Somma, F. Rota, R. Pivonello, M. C. Savanelli, S. Spiezia, and G. Lombardi
Short-Term Effects of Growth Hormone (GH) Treatment or Deprivation on Cardiovascular Risk Parameters and Intima-Media Thickness at Carotid Arteries in Patients with Severe GH Deficiency
J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2056 - 2062.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
109/20/2405    most recent
01.CIR.0000129763.51060.77v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Randeva, H. S.
Right arrow Articles by Shalet, S. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Randeva, H. S.
Right arrow Articles by Shalet, S. M.
Related Collections
Right arrow Acute coronary syndromes
Right arrow Chronic ischemic heart disease
Right arrow Secondary prevention
Right arrow Mechanism of atherosclerosis/growth factors
Right arrow Pathophysiology

Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2004 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.