Matricellular proteins: new molecular targets to prevent heart failure

Matricellular proteins are highly expressed in reparative responses to pressure and volume overload, ischemia, oxidative stress after myocardial injury, and modulate the inflammatory and fibrotic process in ventricular remodeling, which leads to cardiac dysfunction and eventually overt heart failure. Generally, matricellular proteins loosen strong adhesion of cardiomyocytes to extracellular matrix, which would help cells to move for rearrangement and allow inflammatory cells and capillary vessels to spread during tissue remodeling. Among matricellular proteins, osteopontin (OPN) and tenascin-C (TN-C) are de-adhesion proteins and upregulate the expression and activity of matrix metalloproteinases. These matricellular proteins could be key molecules to diagnose cardiac remodeling and also might be targets for the prevention of adverse ventricular remodeling. This review provides an overview of the role of matricellular proteins such as OPN and TN-C in cardiac function and remodeling, as determined by both in basic and in clinical studies.     

Desialylation of plasma proteins in severe dengue infection: possible role of oxidative stress

Oxidative stress in dengue infection has been suggested. This study was carried out to explore the plasma protein oxidation and its sialic acid content in dengue infection. Thirty-two dengue hemorrhagic fever (DHF), 25 dengue shock syndrome (DSS), 29 dengue fever (DF), and 63 healthy controls were included in this study. The extent of carbonylation, sulphydryl content, and desialylation of plasma protein was estimated in acute phase sample. Significantly higher levels of protein carbonyls and lower levels of sialic acid and sulphydryl groups were found in DHF and DSS compared with DF using one-way analysis of variance. Regression analysis showed that desialylation is dependent on protein carbonyls in DHF/DSS. This study indicates that, in dengue infection, plasma proteins undergo increased levels of desialylation, which can be attributed to the oxidative stress. Future studies on sialylation status of endothelium and platelets can show light into the pathogenesis of the dengue infection.     

STEMI and heart failure in the elderly: role of adverse remodeling

The elderly population (age ≥ 65 years) has been increasing worldwide. In North America and Europe, both heart failure (HF) and ST-segment elevation MI (STEMI) are more prevalent in the elderly. Morbidity, hospitalizations and costs associated with HF are higher in the elderly. Despite improved therapies, the bulk of cardiovascular deaths occur in the elderly. Survivors of acute STEMI develop progressive ventricular remodeling that leads to HF. There are several reasons for the increased HF burden in the elderly. First, there is a lack of clinical trial data exclusively in elderly patients for specific therapy of adverse remodeling post-STEMI and HF with low ejection fraction (HF/low-EF) or HF with preserved ejection fraction (HF/PEF). Second, there is the lack of data on the impact of aging on remodeling during healing post-STEMI and HF. Third, HF therapy in the elderly is more challenging because of aging-specific biological changes and associated comorbidities and polypharmacy. More research on aging and post-STEMI remodeling and clinical trials on post-STEMI remodeling and HF in the elderly are needed, especially in the “older-elderly” population segment aged ≥75 years.     

Glucocorticoid-binding proteins of rat heart cytosol and their possible role in the transfer of glucocorticoids into nuclei

Binding of [³H]glucocorticoids by cytosol and nuclei isolated from rat heart has been studied. Two types of glucocorticoid-binding proteins (binder I and binder II) were found in the heart cytosol of adrenalectomized rats. Binder I is similar in its properties to serum transcortin. It does not bind dexamethasone, has fast kinetics of corticosterone binding, is insensitive to SH-blockers, thermostable (not inactivated at short exposure to 50°C), and precipitates in the range of 40 to 60% saturation by ammonium sulphate. Binder II corresponds in its properties to dexamethasone binding proteins of typical target tissues for glucocorticoids. It is characterized by relatively slow kinetics of dexamethasone binding, is sensitive to SH-blockers, highly thermolabile (inactivated completely at short exposure to 37°C when not bound to steroids) and precipitates at 0 to 25% saturation with ammonium sulphate. Corticosterone was found to exert strong competitive inhibitory effect on the binding of [³H]dexamethasone by binder II which demonstrates approximately equal affinity of this protein to both steroids. Nuclei isolated from hearts of normal rats are not able to accumulate [³H]dexamethasone and [³H]corticosterone in the absence of cytosol at 4°C and 20°C. [³H]Corticosterone in the complex with binder I, in the absence of binder II, is not accumulated by nuclei. Nuclei are able to accumulate [³H]dexamethasone, bound to binder II at 4°C. Accumulation is increased by 4-fold after 20 min incubation at 20°C. An increase in temperature of higher than 20°C or prolongation of incubation over 20 min decreases accumulation of protein-bound dexamethasone by nuclei. Our data demonstrate the role of binder II as a heart cytoreceptor which might participate directly in the transfer of glucocorticoids into cell nuclei.     

Matricellular proteins and survival in patients with pancreatic cancer: A systematic review

Extracellular matrix (ECM) plays a fundamental role in tissue architecture and homeostasis and modulates cell functions through a complex interaction between cell surface receptors, hormones, several bioeffector molecules, and structural proteins like collagen. These components are secreted into ECM and all together contribute to regulate several cellular activities including differentiation, apoptosis, proliferation, and migration. The so-called “matricellular” proteins (MPs) have recently emerged as important regulators of ECM functions.The aim of our review is to consider all different types of MPs family assessing the potential relationship between MPs and survival in patients with pancreatic ductal adenocarcinoma (PDAC).A systematic computer-based search of published articles, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) Statement issued in 2009 was conducted through Ovid interface, and literature review was performed in May 2017. The search text words were identified by means of controlled vocabulary, such as the National Library of Medicine's MESH (Medical Subject Headings) and Keywords.Collected data showed an important role of MPs in carcinogenesis and in PDAC prognosis even though the underlying mechanisms are still largely unknown and data are not univocal. Therefore, a better understanding of MPs role in regulation of ECM homeostasis and remodeling of specific organ niches may suggest potential novel extracellular targets for the development of efficacious therapeutic strategies.     

Oxidative stress in heart failure: the role of mitochondria

Recent experimental and clinical studies have suggested that oxidative stress is enhanced in heart failure. The production of oxygen radicals is increased in the failing heart whereas antioxidant enzyme activities are preserved. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and also a target against oxidant-induced damage. Chronic increases in oxygen radical production in the mitochondria can lead to a catastrophic cycle of mitochondrial DNA damage as well as functional decline, further radical generation, and cellular injury. These cellular events might play an important role in the development and progression of myocardial remodeling and failure.     

Mast cells and epsilonPKC: a role in cardiac remodeling in hypertension-induced heart failure

Heart failure (HF) is a chronic syndrome in which pathological cardiac remodeling is an integral part of the disease and mast cell (MC) degranulation-derived mediators have been suggested to play a role in its progression. Protein kinase C (PKC) signaling is a key event in the signal transduction pathway of MC degranulation. We recently found that inhibition of epsilonPKC slows down the progression of hypertension-induced HF in salt-sensitive Dahl rats fed a high-salt diet. We therefore determined whether epsilonPKC inhibition affects MC degranulation in this model. Six week-old male Dahl rats were fed with a high-salt diet to induce systemic hypertension, which resulted in concentric left ventricular hypertrophy at the age of 11 weeks, followed by myocardial dilatation and HF at the age of 17 weeks. We administered epsilonV1-2, an epsilonPKC-selective inhibitor peptide (3 mg/kg/day), deltaV1-1, a deltaPKC-selective inhibitor peptide (3 mg/kg/day), TAT (negative control; at equimolar concentration; 1.6 mg/kg/day) or olmesartan (angiotensin receptor blocker [ARB] as a positive control; 3 mg/kg/day) between 11 weeks and 17 weeks. Treatment with epsilonV1-2 attenuated cardiac MC degranulation without affecting MC density, myocardial fibrosis, microvessel patency, vascular thickening and cardiac inflammation in comparison to TAT- or deltaV1-1-treatment. Treatment with ARB also attenuated MC degranulation and cardiac remodeling, but to a lesser extent when compared to epsilonV1-2. Finally, epsilonV1-2 treatment inhibited MC degranulation in isolated peritoneal MCs. Together, our data suggest that epsilonPKC inhibition attenuates pathological remodeling in hypertension-induced HF, at least in part, by preventing cardiac MC degranulation.     

The emerging role of microRNAs in cardiac remodeling and heart failure

Recent studies have suggested a potentially important role for a family of tiny regulatory RNAs, known as microRNAs (miRNAs or miRs), in the control of diverse aspects of cardiac function in health and disease. Although the field of miRNA biology is relatively new, there is emerging evidence that miRNAs may play an important role in the pathogenesis of heart failure through their ability to regulate the expression levels of genes that govern the process of adaptive and maladaptive cardiac remodeling. Here, we review the biology of miRNAs in relation to their role in modulating various aspects of the process of cardiac remodeling, as well as discuss the potential application of miRNA biology to the field of heart failure.     

Cell size and communication: role in structural and electrical development and remodeling of the heart.

With the advent of new information about alterations of cardiac gap junctions in disease conditions associated with arrhythmias, there have been major advances in the genetic and metabolic manipulation of gap junctions. In contrast, in naturally occurring cardiac preparations, little is known about cell-to-cell transmission and the subcellular events of propagation or about structural mechanisms that may affect conduction events at this small size scale. Therefore, the aim of this article is to review results that produce the following unifying picture: changes in cardiac conduction due to remodeling cardiac morphology ultimately are limited to changes in three morphologic parameters: (1) cell geometry (size and shape), (2) gap junctions (distribution and conductivity), and (3) interstitial space (size and distribution). In this article, we consider changes in conduction that result from the remodeling of cell size and gap junction distribution that occurs with developmental ventricular hypertrophy from birth to maturity. We then go on to changes in longitudinal and transverse propagation in aging human atrial bundles that are produced by remodeling interstitial space due to deposition of collagenous septa. At present, experimental limitations in naturally occurring preparations prevent measurement of the conductance of individual gap junctional plaques, as well as the delays in conduction associated with cell-to-cell transmission. Therefore, we consider the development of mathematical electrical models based on documented cardiac microstructure to gain insight into the role of specific morphologic parameters in generating the changes in anisotropic propagation that we measured in the tissue preparations. A major antiarrhythmic implication of the results is that an "indirect" therapeutic target is interstitial collagen, because regulation of its deposition and turnover to prevent or alter microfibrosis can enhance side-to-side electrical coupling between small groups of cells in aging atrial bundles.     

Meal-induced oxidative stress and low-density lipoprotein oxidation in diabetes: the possible role of hyperglycemia

Oxidative stress and its contribution to low-density lipoprotein (LDL) oxidation have been implicated in the pathogenesis of vascular diabetic complications. However, the relationship between hyperglycemia, hyperinsulinemia, hyperlipidemia, and oxidative stress is still debated. If plasma glucose and/or insulin and/or lipid are some of the most important determinants of oxidative stress in diabetes, then their typical postprandial elevations in diabetes would be expected to favor oxidative stress and LDL oxidation. To test this hypothesis, in type 2 diabetic patients, we evaluated the effects of two different standard meals designed to produce different levels of postprandial hyperglycemia on the plasma oxidative status and LDL oxidation. The meals were administered in randomized order to each of 10 type 2 diabetic patients. Blood samples were collected at baseline and 60 and 120 minutes after the meals. In every sample, plasma levels of glucose, insulin, cholesterol, triglycerides, nonesterified fatty acids (NEFAs), malondialdehyde (MDA), and the total radical-trapping antioxidant parameter (TRAP) were measured. LDL susceptibility to oxidation was evaluated at baseline and after 120 minutes. Plasma glucose, insulin, triglycerides, and MDA increased and NEFAs and TRAP significantly decreased after either meal. The variations in plasma glucose, MDA, and TRAP were significantly greater and LDL was more susceptible to oxidation after the meal that produced a significantly higher degree of hyperglycemia. These results suggest that postprandial hyperglycemia may contribute to oxidative stress in diabetic patients, providing a mechanistic link between hyperglycemia and diabetic vascular disease.     

Myocyte nuclear and possible cellular hyperplasia contribute to ventricular remodeling in the hypertrophic senescent heart in humans

Objectives. The present investigation was designed to evaluate the growth reserve capacity of the aged and senescent myocardium.Background. Aging affects the ability of the heart to sustain alterations in ventricular loading, and this phenomenon may be coupled with attenuation of the hypertrophic reaction of the myocardium. However, because myocyte cellular hyperplasia has been documented experimentally in the old heart, a similar adaptation may also occur in humans and play a role in this process.Methods. The changes in number and size of ventricular myocytes were measured quantitatively in pathologic hearts of elderly subjects. Morphometric methodologies were applied to the analysis of 13 hypertrophic hearts obtained at autopsy from patients 80 ± 4 (mean ± SD) years old. An identical number of nonhypertrophic hearts collected from subjects 76 ± 7 years old were used as control hearts.Results. A 71% increase in left ventricular weight was associated with a 33% increase in average myocyte cell volume per nucleus and a 36% augmentation in the total number of myocyte nuclei in the ventricular myocardium. However, a 55% increase in right ventricular weight was the result of a 59% increase in the aggregate number of myocyte nuclei, with no change in myocyte cell volume. These cellular processes were associated with a 95% and 83% enlargement of the myocardial interstitium in the left and right ventricle, respectively.Conclusions. Myocyte nuclear and possibly cellular hyperplasia appear to be the prevailing growth mechanism of the overloaded aging myocardium. Proliferation of myocyte nuclei and connective tissue accumulation are the major determinants of ventricular remodeling in the hypertrophic senescent heart.     

Interaction between chemokines and oxidative stress: possible pathogenic role in acute coronary syndromes

OBJECTIVES: We sought to study the relationships between chemokines and oxidative stress in acute coronary syndrome. BACKGROUND: In view of existing knowledge on the participation of leukocytes and oxidative stress in the pathogenesis of acute coronary syndrome, we hypothesized that chemokines may play a role in recruiting and activating leukocytes in this disorder. METHODS: The levels of chemokines and oxidative stress were studied in 38 patients with stable and 38 with unstable angina and in 20 controls. In separate in vitro experiments the effect of chemokines on reactive oxygen species in monocytes and the effect of antioxidants on chemokine levels in these cells were also studied. RESULTS: 1) Angina patients had raised serum levels of chemokines in both cross-sectional and longitudinal testing, with particularly high levels of interleukin (IL)-8, monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory peptide (MIP)-1-alpha in unstable disease. 2) T cells, and particularly monocytes, seem to contribute to the raised IL-8, MCP-1 and MIP-1-alpha levels in unstable angina. 3) Concomitantly, and significantly correlated with MCP-1 and IL-8 levels, stable and particularly unstable angina patients had decreased plasma levels of antioxidants and increased lipid peroxidation, suggesting enhanced oxidative stress. 4) Monocyte chemoattractant protein-1 enhanced the generation of O2- in monocytes from unstable angina patients, and the antioxidant glutathione-monoethyl ester suppressed the production of IL-8 and MCP-1 in these cells. CONCLUSIONS: Our findings suggest an interaction between chemokines and oxidative stress in unstable angina. This interaction may represent a vicious circle involved in the pathogenesis of acute coronary syndromes.     

Inflammatory cytokines and the possible immunological role for lipoproteins in chronic heart failure

AIMS: We studied the clinical and immunological importance of fasting cholesterol, HDL, LDL and triglycerides in patients with chronic heart failure in relation to plasma concentrations of tumor necrosis factor-alpha (TNFalpha), soluble TNF receptor-1 and -2 (sTNF-R1 and -R2), and a ratio potentially indicating recent endotoxin bioactivity (soluble [s] CD14/total cholesterol). METHODS AND RESULTS: Fifty-eight stable, non-oedematous patients with established heart failure and 19 controls were studied prospectively. Concentrations of sTNF-R1 and sCD14 were higher in patients than in controls (1238+/-96 vs. 632+/-72 pg/ml, P=0.005 and 3401+/-120 vs. 2775+/-139 pg/ml, P=0.007, respectively), whereas those of TNFalpha (9.3+/-1.1 vs. 6.7+/-0.6 pg/ml) and sTNF-R2 (2464+/-145 vs. 1920+/-303 pg/ml) were not. Cholesterol (5.6+/-0.1 vs. 5.5+/-0.2 mmol/l) and LDL (3.5+/-0.1 vs. 3.6+/-0.2 mmol/l) were not different (both P>0.75). Patients had lower HDL (1.10+/-0.04 vs. 1.4+/-0.06 mmol/l, P=0.0004) and higher triglycerides (2.1+/-0.1 vs. 1.1+/-0.1 mmol/l, P=0.0006). Aetiology and the presence of cardiac cachexia did not influence the lipid profile. Correlations in patients: cholesterol vs. TNFalpha (r=-0.40, P=0.003), vs. sTNF-R1 (r=-0.24, P=0.08), vs. sTNF-R2 (r=-0.29, P<0.04); sCD14 vs. TNFalpha (r=0.44, P=0.005), vs. sTNF-R1: (r=0.65, P<0.0001), vs. sTNF-R2 (r=0.59, P<0. 0001). The sCD14/cholesterol ratio related powerfully to TNFalpha (r=0.60), sTNF-R1 (r=0.74), and sTNF-R2 (r=0.65, all P<0.0001). This sCD14/cholesterol ratio emerged as the strongest predictor of TNFalpha, sTNF-R1 and -R2 (all P<0.01), independently of renal and hepatic function, and conventional measures of disease severity. A cholesterol level <5.2 mmol/l (n=18) significantly predicted a poor clinical outcome (P<0.04, RR 3.5, 95% CI 1.1-11.0) independently of peak VO(2) (P=0.07), NYHA class (P=0.08), aetiology (P=0.14), and age, body wasting, sodium, LVEF, heart rate, and blood pressure (all P>0.20, follow-up 12 months, event rate 26%). CONCLUSION: Our data supports previous findings that lower, rather than higher cholesterol levels are associated with poor clinical outcome in patients with chronic heart failure. This relationship is unrelated to heart failure aetiology, and suggests that the classic risk profile is not longer relevant in established heart failure. The little-recognised ability of all lipoprotein fractions to bind endotoxin and to serve as natural buffer substances may explain this relationship between lower lipoprotein levels, higher cytokine concentrations and impaired prognosis.     

Oxidative stress in pulmonary fibrosis: a possible role for redox modulatory therapy

Idiopathic ulmonary fibrosis (histopathology of usual interstitial pneumonia) is a progressive lung disease of unknown etiology. No treatment has been shown to improve the prognosis of the patients with this disease. Recent evidence, including the observations that the patients with idiopathic pulmonary fibrosis have higher levels of oxidant stress than control patients, and a recent multicenter European study examining the effect of the antioxidant N-acetylcysteine on the progression of idiopathic pulmonary fibrosis suggest that the cellular redox state may play a significant role in the progression of this disease. These complex mechanisms include activation of growth factors as well as regulation of matrix metalloproteinases and protease inhibitors. Potential future approaches for the therapy of interstitial pulmonary fibrosis may involve synthetic agents able to modulate cellular redox state. Investigation into therapeutic approaches to inhibit oxidant-mediated reactions in the initiation and progression of pulmonary fibrosis may provide hope for the future treatment of this disease.