Cardiac Matrix Remodeling Research Articles

P300 in Cardiac Development and Accelerated Cardiac Aging.

The heart is the first functional organ that develops during embryonic development. While a heartbeat indicates life, cessation of a heartbeat signals the end of life. Heart disease, due either to congenital defects or to acquired dysfunctions in adulthood, remains the leading cause of death worldwide. Epigenetics plays a key role in both embryonic heart development and heart disease in adults. Stress-induced vascular injury activates pathways involved in pathogenesis of accelerated cardiac aging that includes cellular dysfunction, pathological cardiac hypertrophy, diabetic cardiomyopathy, cardiac matrix remodeling, cardiac dysfunction and heart failure. Acetyltransferase p300 (p300), a major epigenetic regulator, plays a pivotal role in heart development during embryogenesis, as deficiency or abnormal expression of p300 leads to embryonic death at early gestation periods due to deformation of the heart and neural tube. Acetyltransferase p300 controls heart development through histone acetylation-mediated chromatin remodeling and transcriptional regulation of genes required for cardiac development. In adult hearts, p300 is differentially expressed in different chambers and epigenetically controls cardiac gene expression. Deregulation of p300, in response to prohypertrophic and profibrogenic stress signals, is associated with increased recruitment of p300 to several genes including transcription factors, increased acetylation of specific lysines in histones and transcription factors, altered chromatin organization, and increased hypertrophic and fibrogenic gene expression. Cardiac hypertrophy and myocardial fibrogenesis are common pathological manifestations of several stress-induced accelerated cardiac aging-related pathologies, including high blood pressure-induced or environmentally induced cardiac hypertrophy, myocardial infarction, diabetes-induced cardiomyopathy, and heart failure. Numerous studies using cellular and animal models clearly indicate that pharmacologic or genetic normalization of p300 activity has the potential to prevent or halt the progression of cardiac aging pathologies. Based on these preclinical studies, development of safe, non-toxic, small molecule inhibitors/epidrugs targeting p300 is an ideal approach to control accelerated cardiac aging-related deaths worldwide.

YAP activation promotes the transdifferentiation of cardiac fibroblasts to myofibroblasts in matrix remodeling of dilated cardiomyopathy

Yes-associated protein (YAP) is an important regulator of cellular proliferation and transdifferentiation. However, little is known about the mechanisms underlying myofibroblast transdifferentiation in dilated cardiomyopathy (DCM). We investigated the role of YAP in the pathological process of cardiac matrix remodeling. A classic model of DCM was established in BALB/c mice by immunization with porcine cardiac myosin. Cardiac fibroblasts were isolated from neonatal Sprague-Dawley rats by density gradient centrifugation. The expression levels of α-smooth muscle actin (α-SMA) and collagen volume fraction (CVF) were significantly increased in DCM mice. Angiotensin II (Ang II)-mediated YAP activation promoted the proliferation and transdifferentiation of neonatal rat cardiac fibroblasts, and this effect was significantly suppressed in the shRNA YAP + Ang II group compared with the shRNA Control + Ang II group in vitro (2.98±0.34 ×105 vs 5.52±0.82 ×105, P<0.01). Inhibition of endogenous Ang II-stimulated YAP improved the cardiac function by targeting myofibroblast transdifferentiation to attenuate matrix remodeling in vivo. In the valsartan group, left ventricular ejection fraction and fractional shortening were significantly increased compared with the DCM group (52.72±5.51% vs 44.46±3.01%, P<0.05; 34.84±3.85% vs 26.65±3.12%, P<0.01). Our study demonstrated that YAP was a regulator of cardiac myofibroblast differentiation, and regulation of YAP signaling pathway contributed to improve cardiac function of DCM mice, possibly in part by decreasing myofibroblast transdifferentiation to inhibit matrix remodeling.

Galectin-3: A Heart Failure Biomarker as Sign of Active Coronary Heart Disease

Atherosclerosis is characterized by the accumulation of cholesterol esters, macrophages and fibrous elements on the inner artery wall. This process begins with accumulation of plasma lipoproteins on the inner wall of the artery, which leads to changes in the passage and elasticity of the blood vessels. Monocytes penetrating the arterial wall transforms into macrophages which digest cholesterol and form foam cells which is one of the first steps in atherosclerotic process. Activation of macrophages is affected by galectin-3, a β-galactoside-binding lectin which is also involved in cardiac remodeling. Cardiac matrix remodeling is the ultimate result of macrophages proliferation and chemotaxis, neutrophil extravasation, oxidative stress, apoptosis, angiogenesis, fibroblast proliferation and deposition of collagen. Studies show that elevated levels of galectin 3 within atherosclerotic lesions in humans are closely related to the development of a disease itself. With this review, we want to demonstrate the correlation between galectin-3 which is precipitated in atherosclerotic plaque and has an influence on the development of cardiovascular diseases and its role in the prognosis of recovery in cardiac patients.

What Is Measured by Cardiac Fibrosis Biomarkers and Imaging?

Cardiac fibrosis is the consequence of extracellular cardiac matrix remodeling resulting from pathological processes, including ischemia, stretch, inflammation, and neurohormonal activation. Fibrosis can be reparative or reactive. At the site of a transmural myocardial infarction, fibrotic scarring provides protective strength and prevents myocardial rupture. Diffuse reactive fibrosis occurs remotely from the ischemic scar. It is associated with myocyte hypertrophy and contributes to the detrimental process of remodeling, increased ventricular stiffness, tissue disarray with consequent contractile heterogeneity, reduced contractile reserve, and arrhythmogenic anisotropy. Although most commonly found in the setting of ischemic heart disease, where it acts as a precursor to heart failure (HF), the more diffuse type of fibrosis is also an essential feature of idiopathic dilated cardiomyopathy, diabetic cardiomyopathy, hypertensive heart disease, and hypertrophic cardiomyopathy (HCM). Cardiac fibrosis results in an accumulation of proteins including collagen in the extracellular space, damage that has previously been considered irreversible in many cardiovascular (CV) diseases. It is now emerging as an important novel target for future CV antifibrotic therapies.1,2 Promising therapeutic candidates include antihypertensive therapies, antialdosterone agents, anti-inflammatory and antioxidant agents, growth factor inhibitors, matricellular proteins, and key miRNAs, as well as cell therapy or genetic interventions. It is therefore important to noninvasively identify, measure, image, and monitor the degree of cardiac fibrosis to better understand its pathophysiology and select optimal patients for antifibrotic therapy trials. Furthermore, noninvasive surrogate end points such as circulating biomarkers or magnetic resonance and molecular imaging should allow for larger proof-of-concept clinical trials than previously possible with endomyocardial biopsies. Article see p 271 Detection of cardiac fibrosis is based on the quantification of a diffuse excess of collagen fiber deposition in the interstitial space, as assessed by staining techniques. Fibrosis may also be monitored noninvasively using biochemical assessments at circulating levels of collagen substrates, …

MiR‐17 targets tissue inhibitor of metalloproteinase 1 and 2 to modulate cardiac matrix remodeling

We aimed to investigate the role of miR-17 in cardiac matrix remodeling following myocardial infarction (MI). Using real-time PCR, we quantified endogenous miR-17 in infarcted mouse hearts. Compared with related microRNAs, miR-17 was up-regulated most dramatically: 3.7-fold and 2.4-fold in the infarct region 3 and 7 d post-MI, respectively, and 2.4-fold in the border zone at d 3 compared to sham control (P<0.01). Chimeric luciferase reporter constructs were cloned for miR-17 target validation. miR-17 targeted the 3'-UTR of TIMP2 and the protein coding region of TIMP1. The miR-17 mimic decreased TIMP2 (P<0.01) and TIMP1 (P<0.05) protein expression compared with the scrambled control. Inhibition of endogenous miR-17 by in vivo antagomir delivery enhanced TIMP2 (P<0.01) and TIMP1 (P<0.05) protein expression compared to the mismatch group, decreased MMP9 activity (P<0.05), reduced infarct size as early as 7 d post-MI (P<0.05), and improved cardiac function (fractional shortening and fractional area contraction, P<0.05) at d 21 and 28 post-MI. Transgenic mice overexpressing miR-17 in the heart confirmed the deleterious role of miR-17 in matrix modulation. Our study suggests that miR-17 participates in the regulation of cardiac matrix remodeling and provides a novel therapeutic approach using miR-17 inhibitors to prevent remodeling and heart failure after MI.

TIMP-2 mutant decreases MMP-2 activity and augments pressure overload induced LV dysfunction and heart failure

Pressure overload induces cardiac extracellular matrix (ECM) remodelling and results in heart failure. ECM remodelling by matrix metalloproteinases (MMPs) is primarily regulated by their target inhibitors, tissue inhibitor of matrix metalloproteinases (TIMPs). It is known that TIMP-2 is highly expressed in myocardium and is required for cell surface activation of pro-MMP-2. We and others have reported that imbalance between angiogenic growth factors and anti-angiogenic factors results in transition from compensatory cardiac hypertrophy to heart failure. We previously reported the pro-angiogenic role of MMP-2 in cardiac compensation, however, the specific role of TIMP-2 during pressure overload is yet unclear. We hypothesize that genetic ablation of TIMP-2 exacerbates the adverse cardiac matrix remodelling due to lack of pro-angiogenic MMP-2 and increase in anti-angiogenic factors during pressure overload stress and results in severe heart failure. To verify this, ascending aortic banding (AB) was created to mimic pressure overload, in wild type C57BL6/J and TIMP-2-/- (model of MMP-2 deficiency) mice. Left ventricular (LV) function assessed by echocardiography and pressure-volume loop studies showed severe LV dysfunction in TIMP-2-/- AB mice compared to controls. Expression of MMP-2, vascular endothelial growth factor (VEGF) was decreased and expression of MMP-9, anti-angiogenic factors endostatin and angiostatin was increased in TIMP-2-/- AB mice compared with wild type AB mice. Connexins (Cx) are the gap junction proteins that are widely present in the myocardium and play an important role in endothelial-myocyte coupling. Our results showed that expression of Cx 37 and 43 was decreased in TIMP-2-/- AB mice compared with corresponding wild type controls. These results suggest that genetic ablation of TIMP-2 decrease the expression of pro-angiogenic MMP-2, VEGF and increases anti-angiogenic factors that results in exacerbated abnormal ventricular remodelling leading to severe heart failure.

The Detection of Myocardial Fibrosis

Both type 1 and type 2 diabetes mellitus (DM) are associated with a significant increase in cardiovascular risk. Glycemic control has, unfortunately, not been convincingly shown to reduce cardiovascular risk.1–3 The level at which blood pressure should be controlled also is controversial.4 Thus, there may be a need to focus on new therapeutic targets if we are to reduce cardiovascular risk in patients with either type 1 or type 2 DM. Cardiac and large arteries fibrosis is a frequent occurrence in patients with DM and one of the major factors predisposing to the development of heart failure (HF). Cardiac fibrosis is the consequence of extracellular cardiac matrix remodeling resulting from pathological processes, including ischemia; stretch; inflammation; and specifically in DM, oxidative stress, advanced glycation end products, and several neurohormonal mediators. Cardiac fibrosis may cause myocyte slippage, tissue heterogeneity and dyssynchrony, ventricular dilatation, and contractile dysfunction. Myocardial fibrosis alters myocardial compliance, and associated fibrosis-related large artery stiffness may predispose to diastolic dysfunction and HF with a preserved left ventricular ejection fraction. Cardiac fibrosis also may result in alteration of gap junctions and predispose to arrhythmias and sudden cardiac death.5 Bioimaging and biomarkers of cardiac fibrosis, therefore, may become clinically useful tools, particularly given the potential for cardioprotective and cardioreparative pharmacological strategies.6,7 Article see p 51 The measurement of various serum peptides arising from the metabolism of collagen types I and III, of degradation fragments (carboxy-terminal telopeptide of type I collagen), and of specific metalloproteinases may provide a noninvasive assessment of fibrosis.8–10 A strong correlation exists between changes in serum levels of biomarkers for the turnover of extracellular cardiac matrix proteins and ongoing cardiac remodeling. Diagnostic approaches for diabetic cardiomyopathy …

180 microrna-17 Accelerates Cardiac Matrix Remodeling After Myocardial Infarction by Targeting Timp-1 and Timp-2

The effects of microRNA-17 (miR-17) have been reported for some disease processes, but its regulation of cardiac matrix remodeling following myocardial infarction (MI) has not been extensively investigated.

Plasma metalloproteinase levels are dysregulated in signal transducer and activator of transcription 3 mutated hyper-IgE syndrome

Plasma metalloproteinase levels are dysregulated in signal transducer and activator of transcription 3 mutated hyper-IgE syndrome

Cardiac matrix remodeling following intracoronary cell transplantation in dilated cardiomyopathic rabbits

Cellular cardiomyoplasty has been proposed as a promising therapeutic strategy for chronic heart failure. Previous studies focused on structural changes in cardiomyocytes to explain the potential benefits for contractile function. However, limited information is available about the cardiac matrix remodeling following cell transplantation in dilated cardiomyopathy (DCM). Here, we established a new animal model of intracoronary bone marrow mononuclear cells (BMMNCs) transplantation to explore extracellular matrix remodeling in adriamycin-induced cardiomyopathic rabbits. In vivo studies demonstrated that BMMNCs transplantation can dramatically delay the progress of collagen metabolism and decrease myocardial collagen volume fraction. The beneficial effects were mediated by attenuating stress-generated over-expression of matrix metalloproteinases (MMPs) in ventricular remodeling. Improved cardiac function may be contributed in part by stem-associated inhibition of extracellular matrix remodeling.

M002 Molecular imaging of cardiac fibrosis with a new fluorescent probes directed against MMPs

Fibrosis plays a central role in maladaptive remodelling processes, especially in the context of cardiovascular diseases. The fibrotic state depends on the balance between matrix metaloproteinases (MMPs) and their inhibitors, which alter the composition of extracellular matrix. Despite the necessity to localise and quantify fibrosis during cardiovascular diseases, only few biological markers of tissue fibrosis exist. Moreover none of them can evaluate fibrosis, in real time, in vivo. Therefore we developed an optical molecular probe (FR91) aimed at targeting cardiac matrix remodeling, with the innovative property of becoming fluorescent after cleavage by both MMP-2 and MMP-14. The present study was designed to validate this probe in cellular and animal models of MMP-2/MMP-14 activation and of fibrosis. Regarding cellular models, murine fibroblasts (3T3) were exposed to 20 ng/ml TGF-b 1 for 24h. RT-PCR and zymography demonstrated increased MMP-2 and MMP-14 expression and activity. Immunofluorescence (IF) showed that 3T3 cells were positive for both MMPs, and this MMP IF signal colocalized with FR91 labelling. Regarding animal models, C57BL/6J mice were subjected to Aortic Stenosis (AS ; constriction of the thoracic aorta to 30-35 % of its basal diameter). After 3 weeks, increased aortic pressure was confirmed and the heart taken out. We observed an increase by 60 % of the left ventricular (LV) mass, and a doubling of cardiomyocyte size. Histological analysis showed a 8 fold higher collagen content in AS mice compared to controls. MMP-2 expression (PCR) was doubled while its activity (zymography) was strongly increased. In parallel MMP-14 expression and activity were also increased. These changes were associated with a concomitant increase in LV fluorescence for FR91 (assessed ex vivo), which was significantly higher in AS vs. control mice. This increased FR91 fluorescence observed in AS mice disappeared after incubation with EDTA which inhibits MMPs activity. Thus, this study demonstrates that FR91 is a specific probe for the detection of increased MMP-2 and -14 activity and may be a unique tool to selectively detect cardiac fibrosis. Further experiments will test the capacity of FR91 to detect cardiac fibrosis in vivo.

Beneficial role of l‐arginine in cardiac matrix remodelling in insulin resistant rats

The study was performed to determine whether sucrose-induced insulin resistance could increase the expression of cardiac matrix metalloproteinases (MMPs), indices of matrix remodelling, and whether the addition of 1.25 g day(-1) of L-arginine (ARG) to a sucrose diet could prevent both the sucrose-induced metabolic abnormalities and elevated cardiac expression of matrix metalloproteinases in an insulin resistant stage that precedes frank type 2 diabetes. Experiments were performed on 38 male Sprague-Dawley rats, 16 rats maintained a standard chow diet (ST), 12 rats were switched to a sucrose enriched diet (SU) and 10 rats to a sucrose plus L-arginine (1.25 g day(-1)) enriched diet (SU + ARG) for a period of 8 weeks. After 8 weeks of different diets, an intravenous glucose tolerance test (IVGTT) was performed and samples were drawn for the measurements of insulin, glucose, triglycerides, free fatty acids (FFA), plasma cyclic guanosine-monophosphate (c-GMP) and retroperitoneal, omental, epididymal fat pad and heart were dissected and weighed. At the end of the study, retroperitoneal fat, heart weight/body weight ratio, fasting plasma glucose, serum insulin, and serum triglyceride levels and integrated insulin area after IVGTT were significantly higher in SU than in SU + ARG and ST. All these parameters were comparable between SU + ARG and ST animals. FFA levels were significantly different among groups, with highest levels in SU and lowest levels in ST. Fasting plasma c-GMP levels and the integrated c-GMP area after IVGTT, an index of nitric oxide activity, were significantly lower in SU than in SU + ARG and ST, the result was similar in SU + ARG and in ST MMP-9 protein expression increased 10.5-fold, MMP-2 protein expression increased 2.4-fold and the expression of tissue inhibitors of metalloproteinase (TIMP-1) increased 1.7-fold in SU rats as compared to ST animals. This was accompanied with a significant increase of cardiac triglyceride concentrations. In contrast, cardiac MMP-9, MMP-2, and TIMP-1 protein expressions were not different between SU + ARG and ST animals. Cardiac triglyceride levels were not significantly different between SU + ARG and ST rats. SU rats developed insulin resistance and hyperlipidaemia, accompanied with increased fat deposition in the heart and enhanced MMP protein expression. Conversely, ARG supplementation prevents these metabolic abnormalities and restored MMP/TIMP-1 balance.

N − 3 PUFAs modulate global gene expression profile in cultured rat cardiomyocytes. Implications in cardiac hypertrophy and heart failure

In cardiac cells the effects of n − 3 PUFAs on the whole genome are still unknown despite their recognized cardioprotective effects and ability to modulate gene expression. We have evaluated the effects of n − 3 PUFAs supplementation on the global gene expression profile in cultured neonatal rat cardiomyocytes, detecting many genes related to lipid transport and metabolism among the upregulated ones. Many of the downregulated genes appeared related to inflammation, cell growth, extracellular and cardiac matrix remodelling, calcium movements and ROS generation. Our data allow to speculate that the cardioprotective effect of n − 3 PUFAs is related to a direct modulation of genes in cardiac cells.

Impact of T Lymphocytes on Cardiac Remodeling in Hypertension

In their intriguing article appearing in this issue of Hypertension , Yu et al1 provide evidence for a role of T lymphocytes in modulating cardiac matrix remodeling resulting from hypertension. The investigators compared the impact of comparable N G-nitro-l-arginine methyl ester (l-NAME)-induced hypertension on cardiac function and matrix composition among 3 strains of mice with widely different T-lymphocyte profiles. They found increased ventricular stiffness, accompanied by enhanced collagen deposition and cross-linking in the strain of mice that were Th2 dominant (BALB/c). In contrast, in mice that were T- (and B-) lymphocyte deficient (C57BL/6 SCID), hypertension resulted in a diminution of collagen content and cross-linking that was generally associated with heart dilation. No changes in ventricular stiffness or collagen were observed in mice that were Th1 dominant (C57BL/6 WT). Because these different responses of the heart to hypertension were observed under pre-existing dissimilar and extreme immune backgrounds, an obvious question is what impact, if any, T lymphocytes have on hypertension-associated cardiac remodeling in more common scenarios. Will it turn out that the well-established neurohormonal input into cardiac remodeling is actually an immunoneurohormal system or only that the neurohormonal component of remodeling is susceptible to modulation by extreme immune conditions? Other than this broad question, several specific questions come to mind from the work of Yu et al.1 First, how relevant is the use of l-NAME to induce hypertension and cardiac remodeling? Chronic pressure overload of the heart in animal models typically induces changes in the heart that include both increased extracellular matrix deposition and so-called compensatory left ventricular hypertrophy because of enlargement of individual …

71 Cardiac matrix remodelling in congestive heart failure: the role of matrix metalloproteinase (MMPs)

71 Cardiac matrix remodelling in congestive heart failure: the role of matrix metalloproteinase (MMPs)

Circulating tumor necrosis factor-alpha and matrix metalloproteinase activities in patients with idiopathic dilated cardiomyopathy: Effects of beta-blocker on cardiac matrix remodeling

Circulating tumor necrosis factor-alpha and matrix metalloproteinase activities in patients with idiopathic dilated cardiomyopathy: Effects of beta-blocker on cardiac matrix remodeling

Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling

Myocardial fibrosis due to maladaptive extracellular matrix remodeling contributes to dysfunction of the failing heart. Further elucidation of the mechanism by which myocardial fibrosis and dilatation can be prevented or even reversed remains of great interest as a potential means to limit myocardial remodeling and dysfunction. Matrix metalloproteinases (MMPs) are the driving force behind extracellular matrix degradation during remodeling and are increased in the failing human heart. MMPs are regulated by a variety of growth factors, cytokines, and matrix fragments such as matrikines. In the present report, we discuss the regulation of MMPs, the role of MMPs in the development of cardiac fibrosis, and the modulation of MMP activity using gene transfer and knockout technologies. We also present recent findings from our laboratory on the regulation of the extracellular MMP inducer (EMMPRIN), MMPs, and transforming growth factor-beta(1) in the failing human heart before and after left ventricular assist device support, as well as the possibility of preventing ventricular fibrosis using different anti-MMP strategies. Several studies suggest that such modulation of MMP activity can alter ventricular remodeling, myocardial dysfunction, and the progression of heart failure. It is therefore suggested that the interplay of MMPs and their regulators is important in the development of the heart failure phenotype, and myocardial fibrosis in heart failure may be modified by modulating MMP activity.