Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Regional variations in the size and shape of isolated myocytes were studied using the two-kidney, one clip (2K1C) renal model of hypertension. Weanling male Sprague-Dawley rats (50 to 75 g) were anesthetized by ketamine (100 mg/kg) during renal artery clipping (0.2 mm internal diameter silver clip) and were then allowed to grow for 6 to 8 weeks, when the blood pressure had stabilized at 180 mmHg. Hearts were removed, weighed and then were perfused with a calcium-free Joklik medium containing collagenase. Isolated myocytes were collected from five regions and fixed in isoosmolar glutaraldehyde: right ventricular free wall (RVFW), right and left halves of the interventricular septum (RIVS, LIVS), and epicardial and endocardial halves of the left ventricular free wall (LEPI, LENDO). Myocyte volume was measured by Coulter Counter. Myocyte length was measured by sonic digitizer. Cross-sectional area was calculated from myocyte volume and length. Tailcuff systolic pressure and heart weight were significantly increased in 2K1C rats as compared to control. Body weights were not different. Cell volume was significantly increased in RIVS, LIVS, LEPI, and LENDO, but not in RVFW. Cell length was not significantly increased in any region. Thus, the 2K1C model showed a predominant left ventricular hypertrophy in which the right half of the septum acted in concert with the left ventricle. The shape of the hypertrophied myocytes, having an increase in volume due to an increase in cross-sectional area but not length, was most consistent with a pressure-induced form of cardiac hypertrophy.
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PMID:Regional myocyte size in two-kidney, one clip renal hypertension. 323 84

To investigate the nature of electrophysiological changes in adult cat cardiac ventricular myocytes that may occur when cells are maintained in primary culture for 1-2 wk, the electrophysiology of cells freshly isolated from collagenase-perfused hearts (day 0 controls) was compared with that of cells maintained in primary culture for up to 14 days 1) on a two-dimensional (2D) surface (laminin-coated coverslips), which allowed for changes in cellular morphology, or 2) in a three-dimensional (3D) alginate matrix, which minimized changes in cell shape. Action potentials and whole cell ionic currents were recorded using a conventional whole cell patch technique. Whereas cellular resting potential and the depth of the "notch" terminating phase 1 were diminished relative to controls in 2D- and 3D-cultured cells, the action potential duration and the incidence of early afterdepolarizations (EADs) were increased relative to controls in 2D- but not in 3D-cultured cells. Corresponding alterations in whole cell ionic currents included a 40% reduction in inwardly rectifying K current (IK1) conductance (GK1) and a 90% reduction in transient outward K current (Ito) conductance (Gto) in 2D- and 3D-cultured cells relative to day 0 controls and a 50% increase in L-type Ca current (ICa-L) conductance (GCa-L) in 2D-cultured cells relative to 3D-cultured cells and day 0 controls. The reduction in Gto in long-term culture was half-maximal by days 7 and 8 and could not be attributed to reduced Ito availability, involvement of a noninactivating Ito, the cell culture procedure itself, or the presence of serum in the culture media. Gto was larger in day 0 cells from a heart with right ventricular hypertrophy than in day 0 normal control cells and was reduced subsequent to placement of cells in 3D culture for 19 days. The results suggest that long-term culture and change in cellular morphology can affect the electrophysiology of cardiac ventricular myocytes.
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PMID:Electrophysiology of adult cat cardiac ventricular myocytes: changes during primary culture. 773 21

The cardiac interstitium is composed of non-myocyte cells embedded in a highly organized extracellular matrix containing a three-dimensional collagen network which serves to maintain the architecture of the myocardium and determines myocardial stiffness. In hypertensive heart disease, a heterogeneity in myocardial structure, created by the altered behaviour of cardiac fibroblasts responsible for collagen synthesis and degradation, can explain the appearance of diastolic and ultimately systolic dysfunction of the left ventricle. In vivo, circulating and myocardial renin-angiotensin systems (RAS) were found to be involved in the regulation of the structural remodelling of the cardiac interstitium. In vitro, in cultured adult rat cardiac fibroblasts, angiotensin II was shown to stimulate collagen synthesis and to inhibit collagenase activity, which is the key enzyme for collagen degradation. In the SHR-model of primary hypertension, left ventricular hypertrophy could be regressed and abnormal myocardial diastolic stiffness, due to interstitial fibrosis, could be restored to normal by inhibition of the myocardial RAS. These antifibrotic or cardioreparative effects of ACE inhibition that occurred irrespective of blood pressure normalization may be valuable in reversing left ventricular diastolic dysfunction in hypertensive heart disease.
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PMID:Renin-angiotensin system and myocardial fibrosis in hypertension: regulation of the myocardial collagen matrix. 828 64

The interstitial space of the myocardium is composed of nonmyocyte cells and a highly organized collagen network which serves to maintain the architecture and mechanical behavior of the myocardial walls. It is the myocardial collagen matrix that determines myocardial stiffness in the normal and structurally remodeled myocardium. In hypertensive heart disease, the heterogeneity in myocardial structure, created by the altered behavior of nonmyocyte cells, particularly cardiac fibroblasts which are responsible for collagen synthesis and degradation, explains the appearance of diastolic and/or systolic dysfunction of the left ventricle that leads to symptomatic heart failure. Several lines of evidence suggest that circulating and myocardial renin-angiotensin systems (RAS) are involved in the regulation of the structural remodeling of the nonmyocyte compartment, including the cardioprotective effects of angiotensin converting enzyme (ACE) inhibition that was found to prevent myocardial fibrosis in the rat with renovascular hypertension. In cultured adult rat cardiac fibroblasts angiotensin II was shown to directly stimulate collagen synthesis and to inhibit collagenase activity, which is the key enzyme for collagen degradation, that would lead to collagen accumulation. In the spontaneously hypertensive rat, an appropriate experimental model for primary hypertension in man, left ventricular hypertrophy could be regressed and abnormal myocardial diastolic stiffness due to interstitial fibrosis could be restored to normal by inhibition of the myocardial RAS. These antifibrotic or cardioreparative effects of ACE inhibition that occurred irrespective of blood pressure normalization may be valuable in reversing left ventricular diastolic dysfunction in hypertensive heart disease.
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PMID:Renin-angiotensin system and myocardial collagen matrix remodeling in hypertensive heart disease: in vivo and in vitro studies on collagen matrix regulation. 851 39

It was the aim of the present study to characterize the hemodynamic, biochemical and morphologic effect of angiotensin II receptor blockade on hypoxia-induced right ventricular hypertrophy in rats. Isolated right ventricular hypertrophy was induced in female Sprague-Dawley rats by intermittent hypoxia (IH; 10% O2, 8 h/day, 5 days/week, 20 days of exposition, n=15). After completion of IH, left- (LV) and right-ventricular (RV) hemodynamic parameters were measured under room air conditions in the intact, thiopental-anesthetized animals with special Millar ultraminiature tipcatheter-manometers. Cardiac output was determined using the thermodilution method. Cell volume (CV) of isolated cardiomyocytes was measured with a Coulter Channellyzer after collagenase cell isolation. The specific activities of the myocardial pentose phosphate pathway enzymes glucose-6-phosphate-dehydrogenase (G-6-PD) and 6-phosphogluconate-dehydrogenase (6-PGD) were determined using a spectrophotometric assay. IH caused a rise in right ventricular systolic pressure (RVSP) from 38.1+/-0.83 to 58.1+/-1.42 mmHg and an increase in the RV weight/body weight ratio (RVW/BW) from 0.884+/-0. 053 to 1.166+/-0.049 mg/g. The activities of G-6-PD and 6-PGD were significantly increased after IH in the RV, but not in the LV. CV was increased from 24 248+/-1193 to 29 541+/-1765 micrometer 3, myocardial cell length was unchanged. IH had no influence on the LV parameters or cardiac output. Co-infusion of the angiotensin II receptor antagonist losartan (LO; 12 mg/kg/d i.p., n=14) during the IH period reduced the rises in RVSP (49.4+/-2.06 mmHg), RVW/BW (0. 99+/-0.072 mg/g), G-6-PD and 6-PGD significantly, but not completely. The increase in CV, however, was prevented (24 524+/-2370 micrometer 3) entirely. We conclude from these data that the IH-induced RV-hypertrophy was primarily of the concentric type. LO attenuated the hypoxia-induced isolated RV hypertrophy and significantly reduced the metabolic response of the RV. The LO effect was most potent with regard to the increase in cardiomyocyte volume.
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PMID:Effects of angiotensin II receptor blockade on hypoxia-induced right ventricular hypertrophy in rats. 940 68

The aim of this study was to investigate the extracellular matrix gene expression in the hypertrophied left ventricular tissue of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, at early and mature ages. Interestingly, with age, a marked increase (+85% and +187% at 25 and 30 weeks of age, respectively, p < 0.01, vs 5 weeks) in matrix metalloproteinase-1 (MMP-1) mRNA levels in SHR and a progressive decrease (-50%, -70%, -78%, -70% at 10, 15, 25 and 30 weeks, respectively, p < 0.01, vs 5 weeks) in WKY were seen. Moreover, mRNA levels were significantly lower in SHR at 5 weeks. The analysis of mRNA expression for the tissue inhibitor of metalloproteinase-1 (TIMP-1) showed a significant increase in WKY (+44% and +44%, vs 15 and 25 weeks, respectively, p < 0.05), whereas there were no significant changes in SHR with development. At 30 weeks TIMP-1 mRNA levels were significantly reduced in SHR. Temporal trends of procollagen alpha1(I) and procollagen alpha1(III) mRNA levels were similar in both strains, but lower levels for procollagen alpha1(III) were found in SHR at 5 and 30 weeks. Although no significant differences were measured between the strains, mRNA levels for fibronectin were found decreased in WKY and increased in SHR with age. The results of the present study suggest an altered balance between collagen deposition and collagen degradation with development in this model of left ventricular hypertrophy and hypertension.
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PMID:Extracellular matrix gene expression in the left ventricular tissue of spontaneously hypertensive rats. 1041 84

It has been suggested that left ventricular fibrosis in spontaneously hypertensive rats (SHR) is the result of both exaggerated collagen synthesis and insufficient collagen degradation. We have shown previously that chronic treatment with the angiotensin II type 1 receptor antagonist losartan results in diminished synthesis of collagen type I molecules and reversal of myocardial fibrosis in SHR. This study was designed to investigate whether losartan also affects the extracellular degradation of collagen type I fibers in the left ventricle of SHR. The study was performed in 30-week-old normotensive Wistar-Kyoto rats (WKY), untreated SHR, and SHR treated with orally administered losartan (20 mg/kg per day) for 14 weeks before they were killed. Ventricular collagenase activity was determined by degradation of [(14)C]collagen with tissue extracts. Ventricular expression of tissue inhibitor of metalloproteinases 1 (TIMP-1) mRNA was analyzed by Northern blot. A histomorphometric study of the left ventricle was performed in all rats. Compared with WKY, SHR exhibited left ventricular hypertrophy, increased (P<0.05) blood pressure, left ventricular collagen volume fraction and TIMP-1 mRNA, and diminished (P<0.05) collagenase activity. After the treatment period, blood pressure was higher (P<0.05) in losartan-treated SHR than in WKY, and no significant differences were noted in the remaining parameters between the 2 strains of rats. Compared with untreated SHR, treated SHR showed no left ventricular hypertrophy, diminished (P<0.05) blood pressure, left ventricular collagen volume fraction and TIMP-1 mRNA, and increased (P<0.05) collagenase activity. These results suggest that the transcription of the TIMP-1 gene is upregulated in the hypertrophied and fibrotic left ventricle of adult SHR. Upregulation of TIMP-1 may account for diminished collagenase activity in the myocardium of those rats. Chronic angiotensin II type 1 receptor blockade with losartan resulted in inhibition of TIMP-1 expression and stimulation of collagenase activity in the left ventricle of SHR. It is proposed that angiotensin II may facilitate myocardial fibrosis in SHR by depressing the collagenase-mediated extracellular degradation of collagen fibers.
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PMID:Chronic AT(1) blockade stimulates extracellular collagen type I degradation and reverses myocardial fibrosis in spontaneously hypertensive rats. 1085 63

The cardiac extracellular matrix (ECM) is a dynamic entity maintaining the structural and functional properties of the myocardium. Little is known about alterations in ECM regulation during controlled induction of compensated left ventricular hypertrophy (LVH) using experimental aortic stenosis. Fifteen growing sheep received supra-coronary banding at an age of 7 +/- 1 months whereas 10 age-matched sheep served as the control group (C). Explantation of the hearts was performed 8.3 +/- 1 months after banding. Gene sequences for sheep matrix metalloproteinase (MMP)-1,-2,-3,-9 and tissue inhibitors (TIMP)-1,-2,-3 were isolated and cloned. Then mRNA and protein gene expression analyses were performed. Concentric LVH with no evidence of heart failure was diagnosed at explantation. Left ventricular mass index (LVMI) was 150 +/- 33 g/m2 (LVH) versus 88 +/- 23 (C) and 82 +/- 21 (baseline) (p < 0.01 versus LVH). Parallel to LVH there was a significant increase in mRNA and protein expression for MMP-1,-2,-3, -9 and for TIMP-1,-2 whereas there was a significant decrease in TIMP-3 gene expression. A close correlation between changes in LVMI and ECM gene expression was found. Compensated LVH goes along with a significant modification of MMP and TIMP gene expression. Alterations in ECM gene expression may be part of the adaptive process during left ventricular remodeling.
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PMID:Extracellular matrix gene expression correlates to left ventricular mass index after surgical induction of left ventricular hypertrophy. 1151 94

Collagen metabolism in the extracellular matrix (ECM) is related to the pathogenesis of cardiovascular stiffness and remodeling in hypertension. We evaluated the association between collagen metabolism markers and the newly developed parameter, brachial-ankle pulse wave velocity (baPWV), in older hypertensive patients with left ventricular hypertrophy (LVH). We performed echocardiography and baPWV measurement using a new device, form PWV/ABI (Colin Medical Technology, Komaki, Japan), and measured plasma levels of markers of collagen metabolism such as procollagen type I C-terminal propeptide (PICP: a marker of collagen synthesis), collagen type I pyridinoline cross-linked C-terminal telopeptide (ICTP: a marker of collagen type I degradation), matrix metalloproteinase-1 (MMP-1: a marker of collagen degradation) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in 46 hypertensive patients with LVH. BaPWV was correlated with the plasma level of PICP (r=0.33, p=0.03) and ICTP (r=0.29, p=0.05) and the total TIMP-1/MMP-1 ratio (an index of collagen turnover; r=0.30, p=0.04). BaPWV was negatively correlated with the E/A ratio of left ventricular inflow (r=-0.36, p<0.05), while baPWV was not correlated with left ventricular mass index (LVMI; r=-0.175, p=0.25) or deceleration time of the mitral E wave (DCT; r=0.15, p=0.31). The measures of hypertensive heart disease, such as the E/A ratio, DCT or LVMI were not correlated with any collagen markers in this study. In multiple regression analysis adjusted for confounding factors such as age, sex, pulse pressure, mean blood pressure, pulse rate, LVMI, E/A ratio and DCT, the positive correlation between baPWV and total TIMP-1/MMP-1 ratio remained significant (p<0.05). In conclusion, arterial stiffness in high-risk older hypertensive patients may involve ECM collagen metabolism.
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PMID:Collagen metabolism in extracellular matrix may be involved in arterial stiffness in older hypertensive patients with left ventricular hypertrophy. 1667 39

Hyperthyroid patients develop left ventricular hypertrophy associated with alterations of several cardiac parameters such as heart rate, cardiac output, cardiac contraction and hemodynamic overload leading to cardiac complications. Although cardiac hypertrophy and contractile abnormality occur, interstitial fibrosis in the heart usually does not take place in hyperthyroid condition. Therefore, in the present study, the mechanism regulating myocardial extracellular matrix (ECM) remodeling in hyperthyroid condition was investigated. Cardiac hypertrophy was developed in Sprague-Dawley rats by administration of 3,5,3'-triiodo-L-thyronine (triiodothyronine, 8 microg/100g BW, ip, SID) and glucocorticosteroid, dexamethasone (DEX, 35 microg/100g BW, po, SID), which is also an inducer of hypertrophy for 15 days. Heart/Body weight ratio and atrial and brain natriuretic peptide mRNAs were significantly increased in both triiodothyronine- and DEX-treated rats compared to control. Collagens-I and -III deposition in the left ventricular sections was reduced in triiodothyronine-treated rats, whereas in DEX-treated animals those were increased compared to control. While mRNA and protein levels of procollagens-I and -III were increased with triiodothyronine (p<0.01), the levels of mature collagens-I and -III were decreased. The levels of the mature collagens were increased with DEX compared to control. MMP-1 activity in the serum and left ventricle was higher with reduced levels of TIMPs-3 and -4 in the left ventricle of triiodothyronine-treated rats. The results suggest that accelerated breakdown of collagens-I and -III by MMP-1 due to suppression of the endogenous TIMPs plays an important role in regulating the ECM in myocardium of hyperthyroid rat.
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PMID:Thyroid hormone induces myocardial matrix degradation by activating matrix metalloproteinase-1. 1727 72


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