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(Circulation. 1998;98:535-540.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Abnormalities of the Extracellular Degradation of Collagen Type I in Essential Hypertension

Concepción Laviades, MD, PhD; Nerea Varo, BSc; Javier Fernández, DSc, MD, PhD; Gaspar Mayor, MD; María J. Gil, DSc; Ignacio Monreal, DSc, MD; ; Javier Díez, MD, PhD

From the Divisions of Nephrology (C.L.) and Cardiology (G.M.), San Jorge General Hospital, Huesca; the Department of Clinical Chemistry, University Clinic (N.V., J.F., M.J.G., I.M.), and Vascular Pathophysiology Unit, School of Medicine (J.D.), University of Navarra, Pamplona; and the Department of Medicine, School of Medicine, University of Zaragoza (J.D.), Spain.

Correspondence to Javier Díez, MD, PhD, Unidad de Fisiopatología Vascular, Facultad de Medicina, C/Irunlarrea s/n, 31080 Pamplona, Spain.

	Abstract

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Background—This study was designed to investigate whether collagen type I degradation is altered in patients with essential hypertension and whether this alteration could be related to disturbances in the serum matrix metalloproteinase pathway of collagen degradation. A second aim of the study was to assess whether some relation exists between serum markers of collagen type I degradation and left ventricular hypertrophy in hypertensive patients.

Methods and Results—We measured serum concentrations of carboxy-terminal telopeptide of collagen type I (CITP) as a marker of extracellular collagen type I degradation, of total matrix metalloproteinase-1 (MMP-1), or collagenase, of total tissue inhibitor of metalloproteinases 1 (TIMP-1), and of MMP-1/TIMP-1 complex in 37 patients with never-treated essential hypertension and in 23 normotensive control subjects. Serum concentrations of free MMP-1 and free TIMP-1 were calculated by subtracting the values of MMP-1/TIMP-1 complex from the values of total MMP-1 and total TIMP-1, respectively. Measurements were repeated in 26 hypertensive patients after 1 year of treatment with the ACE inhibitor lisinopril. Baseline free MMP-1 was decreased (P<0.001) and baseline free TIMP-1 was increased (P<0.001) in hypertensives compared with normotensives. No significant differences were observed in the baseline values of CITP between the 2 groups of subjects. Hypertensive patients with baseline left ventricular hypertrophy exhibited lower values of free MMP-1 (P<0.01) and CITP (P<0.05) and higher (P<0.001) values of free TIMP-1 than hypertensive patients without baseline left ventricular hypertrophy. Treated patients attained an increase (P<0.001) in free MMP-1 and a decrease (P<0.05) in free TIMP-1. In addition, serum CITP was increased (P<0.05) in treated hypertensives compared with normotensive subjects.

Conclusions—These findings suggest that systemic extracellular degradation of collagen type I is depressed in patients with essential hypertension and can be normalized by treatment with lisinopril. A depressed degradation of collagen type I may facilitate organ fibrosis in hypertensive patients, namely, in those with left ventricular hypertrophy.

Key Words: collagen • hypertension • metalloproteinases • peptides • remodeling

	Introduction

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Arterial hypertension is associated with cardiovascular remodeling, which, among other alterations, is characterized by an increase in extracellular matrix content, especially fibrillar collagen type I and type III.^{1 2} This excess of collagen has been proposed as the result of both increased collagen synthesis and unchanged or decreased collagen degradation.^{3 4}

We recently measured the serum concentrations of both the carboxy-terminal propeptide of procollagen type I (PIP) as a marker of extracellular collagen type I synthesis and the carboxy-terminal telopeptide of collagen type I (CITP) as a marker of extracellular collagen type I degradation in adult spontaneously hypertensive rats (SHRs) with left ventricular hypertrophy and myocardial fibrosis.⁵ Whereas the serum concentration of PIP was higher in SHRs than in normotensive Wistar-Kyoto rats, the serum concentration of CITP was similar in the 2 groups of animals. This finding supports the notion that the degradation of collagen type I is not enough to equilibrate the increased synthesis of collagen type I in SHRs.⁶ Abnormally high serum concentrations of PIP have also been found in patients with essential hypertension,⁷ suggesting enhanced collagen type I synthesis in this condition. However, the role of collagen type I degradation in essential hypertension has to be assessed.

The rate-limiting step in the extracellular degradation of collagen is the catalytic cleavage by interstitial collagenase or matrix metalloproteinase 1 (MMP-1).⁸ Interstitial collagenase accounts for the degradation of up to 40% of newly synthesized collagen in different tissues.⁹ The net level of MMP-1 activity is dependent on the relative concentrations of active enzyme and a family of naturally occurring tissue inhibitors of metalloproteinases, namely tissue inhibitor of metalloproteinases 1 (TIMP-1).^{10 11} Recent data suggest that the balance between these 2 substances is important in several disease states characterized by organ fibrosis, such as idiopathic pulmonary fibrosis¹² and liver cirrhosis.¹³

This study was designed to assess in a noninvasive way the degradation of collagen type I in essential hypertension. Accordingly, we determined the serum concentrations of CITP, MMP-1, and TIMP-1 in patients with the disease before and after chronic treatment with the ACE inhibitor lisinopril.

	Methods

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Subjects
The study population consisted of 37 patients with mild to moderate essential hypertension never treated in stage I or II of organ damage¹⁴ and 23 normotensive control subjects. All subjects gave informed consent, and the local committee on human research approved the study protocol.

Conditions associated with alterations in serum levels of CITP (pulmonary fibrosis, liver cirrhosis, osteoporosis, multiple myeloma, osteolytic metastases, systemic glucocorticoid treatment, and renal insufficiency) or with alterations in serum levels of MMP-1 or TIMP-1 (rheumatoid arthritis, cancer, pulmonary fibrosis, and hepatic fibrosis) were excluded after complete medical examinations.

Twenty-six patients received lisinopril as treatment (range, 10 to 20 mg once daily) for 1 year. The therapeutic goal was to achieve systolic blood pressure and diastolic blood pressure of <140 and 90 mm Hg, respectively. After the 12-month treatment, each patient underwent another complete medical examination.

The control group consisted of 23 subjects with blood pressure <140/90 mm Hg in repeated measurements. They were all healthy blood donors of the University Clinic at the University of Navarra.

Clinical Studies
Echocardiographic Study
Two-dimensional, targeted M-mode, and Doppler ultrasound recordings were obtained in each patient as previously described.⁷ Left ventricular mass was calculated from the formula validated by Devereux and Reichek.¹⁵ Left ventricular mass index was obtained by dividing left ventricular mass by body surface area. The relative wall thickness was measured at end diastole as the ratio of 2x(posterior wall thickness/internal dimensions). The presence of left ventricular hypertrophy (LVH) was established either when left ventricular mass index was >111 g/m² for men and 106 g/m² for women or when relative wall thickness was >0.44.¹⁶ Ejection fraction was calculated according to Quinones et al.¹⁷ The following pulsed Doppler measurements were obtained¹⁸ : maximal early transmitral velocity in diastole (V_E) and maximal late transmitral velocity in diastole (V_A). The diagnosis of diastolic dysfunction was established when the ratio V_E/V_A was <1.¹⁸

Biochemical Determinations
The general biochemical parameters were measured by routine laboratory methods. Renal clearance of creatinine was calculated as the product of urine flow rate and the urine creatinine concentration divided by the serum creatinine concentration. Urinary albumin excretion rate for 24-hour urine collection was measured by an immunonephelometric assay (Behring Institute).

Serum samples to determine CITP, MMP-1, and TIMP-1 were taken at the time of clinical studies and stored at -40°C for up to 6 months. No changes were observed in samples analyzed twice.

Serum CITP was determined by radioimmunoassay according to Risteli et al,¹⁹ using a polyclonal antibody specifically directed against the carboxy-terminal CITP (Orion Diagnostica). The interassay and intra-assay variations for determining CITP were <8%. The sensitivity (lower detection limit) was 0.50 µg of CITP/L.

Total serum MMP-1 was determined by a 2-site ELISA method reported by Zhang et al,²⁰ with a monoclonal antibody specific for human MMP-1 (Amersham). This antibody does not cross-react with ₂-macroglobulin. The interassay and intra-assay variations for determining MMP-1 were 13% and 8%, respectively. The sensitivity (lower detection limit) was 1.70 ng of MMP-1/mL.

Total serum TIMP-1 was determined by a 2-site ELISA method described by Kodama et al,²¹ with a monoclonal antibody specific for human TIMP-1 (Amersham). This antibody does not cross-react with either TIMP-2 or TIMP-3. The interassay and intra-assay variations for determining TIMP-1 were 15% and 11%, respectively. The sensitivity (lower detection limit) was 1.25 ng of TIMP-1/mL.

To determine the serum levels of free MMP-1 and free TIMP-1, the serum MMP-1/TIMP-1 complex was also determined by a 2-site ELISA method according to Clark et al,²² with a monoclonal antibody directed against MMP-1 and another monoclonal antibody directed against TIMP-1 (Amersham). The interassay and intra-assay variations for determining the MMP-1/TIMP-1 complex were 15% and 10%, respectively. The sensitivity (lower detection limit) was 1.50 ng of MMP-1/TIMP-1 complex/mL.

The serum levels of free MMP-1 and free TIMP-1 were calculated after subtracting the values of MMP-1/TIMP-1 complex from the values of total MMP-1 and total TIMP-1, respectively.

Statistical Analysis
Values are expressed as mean±SEM. The null hypothesis that a group of values were normally distributed was tested by Shapiro-Wilks' statistic. Student's t test for unpaired data was used to assess the statistical significance between hypertensive patients and normotensive control subjects and between hypertensive patients with and without left ventricular hypertrophy at baseline. Student's t test for paired data was used to assess the statistical significance between hypertensive patients before and after treatment. Scheffé's 2-way ANOVA was used to assess the statistical significance between normotensive control subjects and hypertensive patients before and after treatment with lisinopril. The correlation between continuously distributed variables was tested by univariate regression analysis. A value of P<0.05 was considered statistically significant.

	Results

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Baseline Findings
Clinical Data
The clinical characteristics of normotensive control subjects and hypertensive patients are presented in Table 1. The left ventricular mass index was higher (P<0.01) in hypertensive patients than in normotensive control subjects. LVH was present in 10 patients but in none of the normotensive control subjects. The V_E/V_A ratio was lower (P<0.01) in hypertensive patients than in normotensive control subjects. Diastolic dysfunction was diagnosed in 18 patients but in none of the normotensive control subjects.

View this table: [in this window] [in a new window]   Table 1. Clinical Parameters Determined in Normotensive Control Subjects and Hypertensive Patients

Serum Markers of Extracellular Collagen Type I Degradation
Serum concentration of total MMP-1 was decreased in hypertensive patients compared with normotensive control subjects (50±3 versus 63±1 ng/mL, P<0.01). Serum concentration of MMP-1/TIMP-1 complex was diminished in hypertensives compared with normotensives (23±2 versus 28±1 ng/mL, P<0.05). As shown in Figure 1, serum concentration of free MMP-1 was lower in hypertensive patients than in normotensive control subjects (27.20±0.36 versus 35.30±0.80 ng/mL, P<0.001).

View larger version (12K): [in this window] [in a new window]   Figure 1. Data points show serum concentrations of free MMP-1 in 23 normotensive subjects (NT) and 37 essential hypertensive patients (HT) at baseline. Lines represent mean values obtained in each group of subjects.

Serum concentration of total TIMP-1 was higher in hypertensive patients than in normotensive control subjects (890±42 versus 459±27 ng/mL, P<0.001). Figure 2 shows that serum concentration of free TIMP-1 was increased in hypertensive patients compared with normotensive control subjects (798±27 versus 436±30 ng/mL, P<0.001).

View larger version (12K): [in this window] [in a new window]   Figure 2. Data points show serum concentrations of free TIMP-1 in 23 normotensive subjects (NT) and 37 essential hypertensive patients (HT) at baseline. Lines represent mean values obtained in each group of subjects.

Although hypertensive patients did tend to exhibit a higher serum CITP concentration than normotensive control subjects, the difference was not statistically significant (2.47±0.16 versus 2.17±0.10 µg/L) (Figure 3).

View larger version (11K): [in this window] [in a new window]   Figure 3. Data points show serum concentrations of carboxy-terminal CITP in 23 normotensive subjects (NT) and 37 essential hypertensive patients (HT) at baseline. Lines represent mean values obtained in each group of subjects.

Hypertensives with LVH exhibited lower serum concentrations of total and free MMP-1 (P<0.01), MMP-1/TIMP-1 complex (P<0.05), and CITP (P<0.05) than hypertensives without LVH (Table 2). In contrast, serum concentrations of total and free TIMP-1 were increased (P<0.001) in patients with LVH compared with patients without LVH (Table 2).

View this table: [in this window] [in a new window]   Table 2. Serum Markers of Extracellular Collagen Type I Degradation Determined in Hypertensive Patients With and Without Left Ventricular Hypertrophy at Baseline

Findings After Treatment
Clinical Data
Arterial pressure was normalized and parameters assessing left ventricular mass and dimensions were diminished in patients receiving lisinopril (Table 3). LVH regressed after treatment in 3 of the 6 patients presenting this alteration before treatment. The trend toward normalization of the ratio V_E/V_A did not attain statistical significance (Table 3). Diastolic dysfunction was corrected after treatment in 4 of the 13 patients who presented this alteration at baseline.

View this table: [in this window] [in a new window]   Table 3. Clinical Parameters and Serum Markers of Extracellular Collagen Type I Degradation Determined in Hypertensive Patients Before and After Treatment

Serum Markers of Extracellular Collagen Type I Degradation
Serum concentration of total MMP-1 increased (P<0.05) after 1 year of treatment with lisinopril (Table 3). No significant changes in serum concentration of MMP-1/TIMP-1 complex were observed in treated patients (Table 3). Thus, serum concentration of free MMP-1 increased (P<0.001) after lisinopril treatment (Table 3). Furthermore, the serum concentration of free MMP-1 was higher (P<0.05) in treated hypertensives than in normotensives.

Table 3 shows that serum concentration of total TIMP-1 did tend to decrease with lisinopril treatment. Serum concentration of free TIMP-1 was diminished (P<0.05) after treatment (Table 3). However, the values of this parameter were still higher (P<0.05) in treated hypertensives than in normotensives.

The treatment with lisinopril was associated with a tendency toward an increase in serum concentrations of CITP (Table 3). The value of this parameter was higher (P<0.05) in treated hypertensives than in normotensives.

No significant correlations were found among the parameters measured in this study in the different groups of subjects.

	Discussion

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One finding of the present study is that the serum concentration of CITP is normal in patients with essential hypertension. CITP is a 12-kDa pyridinoline cross-linked telopeptide produced, together with other peptides, when collagen fibrils undergo hydrolysis by MMP-1.⁹ Because a stoichiometric ratio of 1:1 exists between the number of collagen type I molecules degraded and those of CITP released,¹⁹ measurement of the circulating levels of this peptide gives an idea of the extracellular degradation of collagen type I.

Laurent et al²³ proposed that an equilibrium exists between collagen synthesis and degradation to prevent the development of tissue fibrosis. Accordingly, we reported recently that in SHRs with extensive myocardial fibrosis, an increased synthesis of collagen type I is associated with a normal degradation of collagen type I fibrils.^{5 6} Furthermore, we have shown previously that the synthesis of collagen type I molecules is abnormally increased in patients with essential hypertension.⁷ Therefore, the present findings suggest that the intensity of the extracellular degradation of collagen type I is not enough to equilibrate the increased extracellular synthesis of this molecule, and this can result in organ fibrosis (ie, heart, vessels, and kidney) in patients with essential hypertension.

Another finding of this study is that the serum concentration of free MMP-1 is abnormally diminished in patients with essential hypertension. In addition, the serum concentration of free TIMP-1 is abnormally increased in essential hypertensives.

The MMP/TIMP system plays a determinant role in the regulation of collagen tissue turnover. MMP-1 or collagenase is a Zn²⁺- and Ca²⁺-dependent proteinase that degrades structural type I to type III collagen.^{10 11} TIMP-1 is a member of a family of naturally occurring specific inhibitors that block activation of MMP-1 from both its latent form and its catalytic activity.^{10 11} The net level of proteinase activity is therefore dependent on the relative concentrations of free active enzyme and inhibitor.²⁴ It thus can be suggested that collagenase activity is depressed in patients with essential hypertension, and this alteration may be involved in the diminished extracellular degradation of collagen type I fibrils in these patients.

A number of factors, including transforming growth factor-ß (TGF-ß), have been shown to induce the synthesis of MMP-1.²⁴ This fibrogenic cytokine²⁵ reduces the activity of MMP-1 and increases the concentration of TIMP-1.²⁶ Interestingly, increased TGF-ß production and gene expression by peripheral blood monocytes has been described recently in hypertensive patients with cardiovascular remodeling.²⁷ Further studies are required to establish whether an excess of TGF-ß accounts for the diminished MMP-1 and the increased TIMP-1 found in hypertensives in this study.

Another result of the present study is that the extracellular degradative pathway of collagen type I fibrils is more depressed in hypertensives with LVH than in hypertensives without LVH. It must be stressed, however, that the number of patients presenting with LVH was small. On the other hand, it is clear that none of the serum markers measured here are exclusively heart-specific or unambiguously reflect either fibrolysis or fibrosis in hypertensive heart disease. With these limitations borne in mind, it can be hypothesized that hypertensive patients with LVH may represent a particular subset of essential hypertensives characterized by insufficient extracellular collagen type I degradation and, consequently, exaggerated myocardial deposition of collagen type I fibers. This is further supported by findings by Brilla et al²⁸ showing that the activity of MMP-1 is abnormally depressed in the left ventricle of hypertensives with LVH.

We found that serum concentrations of CITP are increased above the normal values in hypertensives chronically treated with the ACE inhibitor lisinopril. Thus, it can be suggested that lisinopril stimulates extracellular collagen degradation in hypertensive patients, as it does in SHRs.²⁹ Because administration of lisinopril is associated with a decrease to normal levels of the synthesis of collagen type I in essential hypertensives,⁷ the present data allow us to propose that chronic ACE inhibition may result in the restoration of the equilibrium between collagen type I synthesis and degradation in arterial hypertension.

MMP-1 concentrations were increased in hypertensives treated with lisinopril. Furthermore, TIMP-1 concentrations decreased in the same patients. Analysis of the individual data shows that the intensity of these changes is independent of the antihypertensive efficacy of the drug. Thus, a nonhemodynamic mechanism can be involved in the ability of lisinopril to modify the MMP-1/TIMP-1 system. Interestingly, angiotensin II mediates the formation of TGF-ß in cardiac cells,³⁰ vascular cells,³¹ and renal cells.³² On the other hand, a number of data suggest that angiotensin II plays a critical role in the disturbances of collagen metabolism in arterial hypertension.³³ Therefore, it can be proposed that lisinopril diminishes angiotensin II–dependent TGF-ß formation and this, in turn, facilitates the equilibrium between MMP-1 and TIMP-1 in hypertensive patients. Nevertheless, the additional possibility exists that this new equilibrium is also due to the increase in bradykinin-mediated prostanoid formation secondary to ACE inhibition. This is based on the observation by Brilla et al³⁴ that prostaglandin E₂ reduces collagen formation by cardiac fibroblasts by inhibiting collagen synthesis and concomitantly enhancing its degradation.

In conclusion, the findings of this study suggest that the extracellular degradation of collagen type I is depressed in essential hypertension. This alteration, in combination with increased synthesis of this fibril-forming molecule, may facilitate the fibrosis of any organ in patients with the disease. This could be of particular relevance in relation to the development of hypertensive organ damage (ie, cardiovascular remodeling and renal sclerosis). The ability of some antihypertensive drugs (ie, ACE inhibitors) to protect from hypertensive organ damage might be partially due to its capacity to stimulate fibrillar collagen degradation in hypertensive patients.

Received January 14, 1998; revision received April 7, 1998; accepted April 16, 1998.

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