Significance of matrix metalloproteinases in norepinephrine-induced remodelling of rat hearts

Briest, Wilfried; Hölzl, Alexander; Raßler, Beate; Deten, Alexander; Baba, Hideo A.; Zimmer, Heinz‐Gerd

doi:10.1016/s0008-6363(02)00700-9

Cited by 44 publications

(42 citation statements)

References 35 publications

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“…Although MMPs degrade ECM proteins, MMP-2 activation is concomitant with cardiac fibrosis in several heart diseases (25,32,34,35). Accordingly, catecholamines induce the synthesis of collagen fragments in a failing heart, which is accompanied by MMP-2 expression/ activation (2,27). Indeed, adrenergic receptor stimulation induces collagen-I expression and MMP-2 expression/activation in fibroblasts (1,5,19,31).…”

Section: Discussionmentioning

confidence: 99%

“…As catecholamines evoke endogenous MMP-2 expression/activation and collagen-I synthesis in fibroblasts (2,19,28,38), we stimulated the cardiac fibroblasts with 10 Ϫ6 M NE to induce the endogenous expression of MMP-2. As shown in Fig.…”

Section: Endogenously Induced Mmp-2 Increases Collagen-i Expression Tmentioning

confidence: 99%

“…For example, the sympathetic nervous system is activated in patients with various heart diseases (12,24,39), which accelerated collagen accumulation and associated with an increased risk for heart failure (3,25). Indeed, several animal studies (2,17) have reported that chronic sympathetic activation induces cardiac fibrosis, including collagen-I accumulation in the ventricular myocardium.…”

mentioning

confidence: 99%

“…Although MMPs degrade ECM proteins, activation of MMP-2 occurs concomitantly with cardiac fibrosis in a failing heart (22, 25, 32, 34 -36). Accordingly, catecholamines have emerged as a pivotal mediator of collagen fragment synthesis in failing hearts, which is accompanied by increased MMP expression (2,14,23,30). Several animal studies (2,9,17,28) have reported that adrenergic receptor signals stimulate collagen-I synthesis and MMP-2 expression/activation in ventricular myocardium.…”

mentioning

confidence: 99%

“…Accordingly, catecholamines have emerged as a pivotal mediator of collagen fragment synthesis in failing hearts, which is accompanied by increased MMP expression (2,14,23,30). Several animal studies (2,9,17,28) have reported that adrenergic receptor signals stimulate collagen-I synthesis and MMP-2 expression/activation in ventricular myocardium. In contrast, in vivo experiments have shown that inhibiting MMP-2 remarkably improves cardiac fibrosis and left ventricular collagen-I mRNA expression in rats with heart failure (4,17,21), suggesting a critical role for this enzyme in cardiac fibrosis.…”

mentioning

confidence: 99%

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Matrix metalloproteinase-2 stimulates collagen-I expression through phosphorylation of focal adhesion kinase in rat cardiac fibroblasts

Hori

Kashimoto

Yonezawa

et al. 2012

American Journal of Physiology-Cell Physiology

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Matrix metalloproteinase-2 stimulates collagen-I expression through phosphorylation of focal adhesion kinase in rat cardiac fibroblasts. Am J Physiol Cell Physiol 303: C947-C953, 2012. First published August 22, 2012; doi:10.1152/ajpcell.00401.2011.-Collagen-I is thought to be the main component of the extracellular matrix in cardiac fibrosis, the accumulation of which occurs with excessive activation of matrix metalloproteinase-2 (MMP-2). MMP-2 degrades the extracellular matrix; however, the relative importance of MMP-2 to collagen-I synthesis in cardiac fibroblasts remains unclear. We investigated whether extracellular activation of MMP-2 regulates collagen-I synthesis and phosphorylation of focal adhesion kinase (FAK) in rat cardiac fibroblasts. Primary cultures of rat cardiac fibroblasts were incubated with purified active MMP-2 to determine whether extracellular MMP-2 affects collagen-I synthesis and FAK phosphorylation in cardiac fibroblasts. Exogenous MMP-2 significantly stimulated FAK (Tyr397) phosphorylation and induced collagen-I expression in a time-dependent manner. Simultaneous treatment with the FAK inhibitor PF573228 abolished exogenous MMP-2-enhanced FAK (Tyr397) phosphorylation and collagen-I expression. Cells were then stimulated with norepinephrine (NE) to investigate whether endogenous MMP-2 could also induce collagen-I expression through FAK (Tyr397) phosphorylation. NE-stimulated endogenous MMP-2 activation in conditioned medium was significantly attenuated by simultaneous treatment with the MMP inhibitor PD166793. Similarly, NE-induced FAK (Tyr397) phosphorylation and collagen-I expression were significantly inhibited by simultaneous treatment with PD166793 or PF573228. Furthermore, MMP-2 knockdown induced by small interfering RNA (siRNA) significantly abolished endogenous MMP-2 expression and activation. MMP-2 siRNA significantly abolished NE-induced FAK (Tyr397) phosphorylation and collagen-I expression. These findings suggest that the extracellular activation of MMP-2 accelerated collagen-I synthesis in rat cardiac fibroblasts and that FAK phosphorylation (Tyr397) plays a pivotal role in MMP-2-stimulated collagen-I synthesis.

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Section: Discussionmentioning

confidence: 99%

Section: Endogenously Induced Mmp-2 Increases Collagen-i Expression Tmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Matrix metalloproteinase-2 stimulates collagen-I expression through phosphorylation of focal adhesion kinase in rat cardiac fibroblasts

Hori

Kashimoto

Yonezawa

et al. 2012

American Journal of Physiology-Cell Physiology

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Exogenous spermine attenuates myocardial fibrosis in diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress and the canonical Wnt signaling pathway

Zhang

et al. 2020

Cell Biology International

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Myocardial fibrosis is one of the main pathological manifestations of diabetic cardiomyopathy (DCM). Spermine (SPM), a product of polyamine metabolism, plays an important role in many cardiac diseases including hypertrophy, ischemia, and infarction, but its role in diabetic myocardial fibrosis has not been clarified. This study aimed to investigate the role of polyamine metabolism, specifically SPM, in diabetic myocardial fibrosis and to explore the related mechanisms. We used intraperitoneal injection of streptozotocin (STZ, 60 mg/kg) in Wistar rats and high glucose (HG, 40 mM) stimulated cardiac fibroblasts (CFs) to established a type 1 diabetes (T1D) model in vivo and in vitro, which were pretreated with exogenous SPM (5 mg/kg per day and 5 μM). The results showed that hyperglycemia induced the expression of the key polyamine synthesis enzyme ornithine decarboxylase (ODC) decreased and the key catabolic enzyme spermidine/spermine N1‐acetyltransferase (SSAT) increased compared with those in the control group. The body weight, blood insulin level, and cardiac ejection function were decreased, while blood glucose, heart weight, the ratio of heart weight to body weight, myocardial interstitial collagen deposition, and endoplasmic reticulum stress (ERS)‐related protein (glucose‐regulated protein‐78, glucose‐regulated protein‐94, activating transcription factor‐4, and C/EBP homology protein) expression in the T1D group were all significantly increased. HG also caused an increased expression of Wnt3, β‐catenin (in cytoplasm and nucleus), while Axin2 and phosphorylated β‐catenin decreased. Exogenous SPM improved the above changes caused by polyamine metabolic disorders. In conclusion, polyamine metabolism disorder occurs in the myocardial tissue of diabetic rats, causing myocardial fibrosis and ERS. Exogenous SPM plays a myocardial protective role via inhibiting of ERS and the canonical Wnt/β‐catenin signaling pathway.

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Reversal of cardiac dysfunction and subcellular alterations by metoprolol in heart failure due to myocardial infarction

Babick

Elimban

Zieroth

et al. 2013

Journal Cellular Physiology

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In order to examine the reversibility of heart failure due to myocardial infarction (MI) by β-adrenoceptor blockade, 12 weeks infarcted rats were treated with or without metoprolol (50 mg/kg/day) for 8 weeks. The depressed left ventricular (LV) systolic pressure, positive and negative rates of changes in pressure development, ejection fraction, fractional shortening and cardiac output, as well as increased LV end-diastolic pressure in 20 weeks MI animals were partially reversed by metoprolol. MI-induced decreases in septum (systolic) thickness as well as increase in LV posterior wall thickness and LV internal diameter were partially or fully reversible by metoprolol. Treatment of MI animals with metoprolol partially reversed the elevated levels of plasma norepinephrine and dopamine without affecting the elevated levels of epinephrine. Although sarcoplasmic reticular (SR) Ca(2+)-uptake, as well as protein content for SR Ca(2+)-pump and phospholamban, were reduced in the infarcted hearts; these changes were partially reversible with metoprolol. Depressed myofibrillar Ca(2+)-stimulated ATPase activity, as well as mRNA levels for SR Ca(2+)-pump, phospholamban and α-myosin heavy chain, were unaffected whereas increased mRNA level for β-myosin heavy chain was partially reversed by metoprolol. The results suggest that partial improvement of cardiac performance by β-adrenoceptor blockade at advanced stages of heart failure may be due to partial reversal of changes in SR Ca(2+)-pump function whereas partial to complete reverse cardiac remodeling may be due to partial reduction in the elevated levels of plasma catecholamines.

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Significance of matrix metalloproteinases in norepinephrine-induced remodelling of rat hearts

Abstract: MMP inhibition leads to myocardial stiffness with negative functional consequences for the RV and LV in NE-treated rat hearts.

Cited by 44 publications

References 35 publications

Matrix metalloproteinase-2 stimulates collagen-I expression through phosphorylation of focal adhesion kinase in rat cardiac fibroblasts

Matrix metalloproteinase-2 stimulates collagen-I expression through phosphorylation of focal adhesion kinase in rat cardiac fibroblasts

Exogenous spermine attenuates myocardial fibrosis in diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress and the canonical Wnt signaling pathway

Reversal of cardiac dysfunction and subcellular alterations by metoprolol in heart failure due to myocardial infarction

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