Dysregulation Of Matrix Metalloproteinases Research Articles

Angiogenesis-related genes may be a more important factor than matrix metalloproteinases in bronchopulmonary dysplasia development.

We characterized the expression profile of angiogenesis-related genes (ARG) and matrix metalloproteinase (MMP) genes in preterm infants, with and without bronchopulmonary dysplasia (BPD). We reanalyzed a gene expression dataset for preterm infants from the Gene Expression Omnibus database using the Gene-Cloud of Biotechnology Information platform. A total of 1,652 genes were differentially (1.2-fold change) expressed: 811 were highly expressed in infants with BPD, and 841 were highly expressed in those without BPD. Twenty-eight and 11 ARGs were upregulated in infants with and without BPD, respectively. Among 27 detected MMPs and TIMPs, MMP8, MMP9, MMP25, TIMP2 and TIMP3 were differently expressed. Levels of THBS1, MMP8, MMP9, MMP25, TIMP2 and TIMP3 increased as severity of BPD and retinopathy of prematurity (ROP) increased, whereas ETS1, LEF1 and SPOCK2 exhibited the opposite trend. Expression of ETS1 and LEF1 had a fitting rate of R2 = 0.849 and P < 0.001. ELISAs showed a positive correlation between THBS1 and CD36 (receptor of THBS1) levels in serum samples from preterm infants. Our study indicates that the upregulation of THBS1 and downregulation of ETS1, LEF1 promotes BPD in preterm infants by disrupting blood vessel formation rather than by dysregulation of MMPs and TIMPs.

Mesenchymal Stem Cell Treatment Prevents Post-Stroke Dysregulation of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases

Background/Aims: Stem cell treatment is one of the potential treatment options for ischemic stroke. We recently demonstrated a protective effect of human umbilical cord blood-derived mesenchymal stem cells (HUCB-MSCs) in a rat model of ischemic stroke. The treatment attenuated apoptosis and prevented DNA damage. A collection of published studies, including several from our laboratory, indicated the induction and detrimental role for several matrix metalloproteinases (MMPs) in post-stroke brain injury. We hypothesized that the HUCB-MSCs treatment after focal cerebral ischemia prevents the dysregulation of MMPs and induces the expression of endogenous tissue inhibitors of metalloproteinases (TIMPs) to neutralize the elevated activity of MMPs. Methods: To test our hypothesis, we administered HUCB-MSCs (0.25 million cells/animal and 1 million cells/animal) intravenously via tail vein to male Sprague-Dawley rats that were subjected to a transient (two-hour) right middle cerebral artery occlusion (MCAO) and one-day reperfusion. Ischemic brain tissues obtained from various groups of rats seven days after reperfusion were subjected to real-time PCR, immunoblot, and immunofluorescence analysis. Results: HUCB-MSCs treatment prevented the induction of MMPs, which were upregulated in ischemia-induced rats that received no treatment. HUCB-MSCs treatment also prevented the induction of TIMPs expression. The extent of prevention of MMPs and TIMPs induction by HUCB-MSCs treatment is similar at both the doses tested. Conclusion: Prevention of stroke-induced MMPs upregulation after HUCB-MSCs treatment is not mediated through TIMPs upregulation.

Novel Potent Proline-Based Metalloproteinase Inhibitors: Design, (Radio)Synthesis, and First in Vivo Evaluation as Radiotracers for Positron Emission Tomography.

As dysregulation of matrix metalloproteinase (MMP) activity is associated with a wide range of pathophysiological processes like cancer, atherosclerosis, and arthritis, MMPs represent a valuable target for the development of new therapeutics and diagnostic tools. We herein present the chiral pool syntheses, in vitro evaluation, and SAR studies of a series of d- and l-proline- as well as of (4R)-4-hydroxy-l-proline-derived MMP inhibitors possessing general formula 1. Some of the synthesized hydroxamic acids were found to be potent MMP inhibitors with IC50 values in the nanomolar range, also demonstrating no off-target effects toward the other tested Zn2+-dependent metalloproteases (ADAMs and meprins). Utilizing the structure of the (2S,4S)-configured 4-hydroxyproline derivative 4, a selective picomolar inhibitor of MMP-13, the radiolabeled counterpart [18F]4 was successfully synthesized. The radiotracer's biodistribution in mice as well as its serum stability were evaluated for assessing its potential use as a MMP-13 targeting PET imaging agent.

Liver Fibrosis in HCV Monoinfected and HIV/HCV Coinfected Patients: Dysregulation of Matrix Metalloproteinases (MMPs) and Their Tissue Inhibitors TIMPs and Effect of HCV Protease Inhibitors.

An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) may contribute to liver fibrosis in patients with hepatitis C (HCV) infection. We measured the circulating levels of different MMPs and TIMPs in HCV monoinfected and HIV/HCV coinfected patients and evaluated the potential for anti-HCV therapy to modulate MMP and TIMP levels in HCV subjects. We analyzed 83 plasma samples from 16 HCV monoinfected patients undergoing dual or triple anti-HCV therapy, 15 HIV/HCV coinfected patients with undetectable HIV load, and 10 healthy donors (HD). Levels of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, TIMP-1, and TIMP-2 were measured by a SearchLight Multiplex Immunoassay Kit. MMP-2 and MMP-9 were the highest expressed MMPs among all the analyzed samples and their levels significantly increased in HCV monoinfected and HIV/HCV coinfected subjects compared to HD. TIMP-1 levels were significantly higher in HCV and HIV/HCV subjects compared to HD and were correlated with liver stiffness. These findings raise the possibility of using circulating TIMP-1 as a non-invasive marker of liver fibrosis in HCV infection. A longitudinal study demonstrated that MMP-9 levels significantly decreased (40% reduction from baseline) in patients receiving dual as well as triple direct-acting antivirals (DAA) anti-HCV therapy, which had no effect on MMP-2, TIMP-1, and TIMP-2. As the dysregulation of MMP-2 and MMP-9 may reflect inflammatory processes in the liver, the decrease of MMP-9 following HCV protease inhibitor treatment suggests a positive effect on the reduction of liver inflammation.

Regulation and involvement of matrix metalloproteinases in vascular diseases.

Matrix metalloproteinases (MMPs) are a family of zinc dependent endopeptidases whose main function is to degrade and deposit structural proteins within the extracellular matrix (ECM). A dysregulation of MMPs is linked to vascular diseases. MMPs are classified into collagenases, gelatinases, membrane-type, metalloelastase, stromelysins, matrilysins, enamelysins, and unclassified subgroups. The production of MMPs is stimulated by factors such as oxidative stress, growth factors and inflammation which lead to its up- or down-regulation with subsequent ECM remodeling. Normally, excess activation of MMPs is controlled by their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). An imbalance of MMPs and TIMPs has been implicated in hypertension, atherosclerotic plaque formation and instability, aortic aneurysms and varicose vein wall remodeling. Also, recent evidence suggests epigenetic regulation of some MMPs in angiogenesis and atherosclerosis. Over the years, pharmacological inhibitors of MMPs have been used to modify or prevent the development of the disease with some success. In this review, we discuss recent advances in MMP biology, and their involvement in the manifestation of vascular disease.

Metalloproteinase Changes in Diabetes.

Matrix metalloproteinases (MMPs) constitute a group of over 20 structurally-related proteins which include a Zn(++) ion binding site that is essential for their proteolytic activities. These enzymes play important role in extracellular matrix turnover in order to maintain a proper balance in its synthesis and degradation. MMPs are associated to several physiological and pathophysiological processes, including diabetes mellitus (DM). The mechanisms of DM and its complications is subject of intense research and evidence suggests that MMPs are implicated with the development and progression of diabetic microvascular complications such as nephropathy, cardiomyopathy, retinopathy and peripheral neuropathy. Recent data has associated DM to changes in the tendon structure, including abnormalities in fiber structure and organization, increased tendon thickness, volume and disorganization obtained by image and a tendency of impairing biomechanical properties. Although not fully elucidated, it is believed that DM-induced MMP dysregulation may contribute to structural and biomechanical alterations and impaired process of tendon healing.

Progenitor Cells, Bone Marrow–Derived Fibrocytes and Endothelial-to-Mesenchymal Transition

See related article, pp 461–468 Tissue fibrosis, defined as an excessive accumulation of extracellular matrix (ECM) components leading to the destruction of organ architecture and impaired function, affects virtually every tissue and organ in the body, including the arteries. Vascular fibrosis of small and large arteries contributes to arterial remodeling, important in the development and complications of hypertension.1 Fibrogenesis is an active process that involves accumulation of structural proteins (collagen and fibronectin) and adhesion proteins (laminin and fibronectin), expression of adhesion molecules and integrins, and remodeling of the ECM.2 Healthy arteries are surrounded by perivascular adventitial tissue comprising collagens I and III in the intima, media, and adventitia, with collagen types I, III, IV, and V in the endothelial and vascular smooth muscle cell basement membranes.3 These fibrillar proteins maintain vascular integrity and normal vascular tone and function. In hypertension, accumulation of collagen and fibronectin and ECM reorganization lead to increased stiffness of the vessel wall.4 Initially, these processes are adaptive and reversible and may compensate for higher blood pressures, but with time and progressive increases in blood pressure, this becomes maladaptive and decompensated, leading to arterial stiffness that contributes to hypertension-associated target organ damage. These events have been demonstrated in many experimental models of hypertension and in hypertensive patients and have been attributed to activation of ERK1/2, p38mitogen-activated protein kinase, transforming growth factor-β, SMAD pathways, oxidative stress, and dysregulation of matrix metalloproteinases.2 Decreased activation of matrix metalloproteinases and increased activity of tissue inhibitors of metalloproteinase leads to reduced collagen turnover and consequent accumulation, with thickening and remodeling of the vascular wall. Vascular fibrosis is a dynamic and active phenomenon, where a proinflammatory, oxidative milieu, triggered by prohypertensive stimuli, lays the foundation for fibrosis and activation of ECM-producing cells. Until recently the process seemed fairly …

Role of Matrix Metalloproteinases in Animal Models of Ischemic Stroke

Matrix metalloproteinases (MMP) comprise a family of at least 25 zinc-dependent endopeptidases that play a pivotal role in the physiopathology of the mammalian central nervous system. In the first phases after stroke, the dysregulation of MMPs has been described to increase acute neurovascular disruption and cerebral injury. In particular, MMP-mediated alterations lead to blood-brain barrier (BBB) leakage, cerebral edema, hemorrhage, leukocyte infiltration and progressive inflammatory reactions underlying brain tissue loss. In addition, MMPs have been also shown to play critical activities during the repair phases of cerebral ischemia, particularly during angiogenesis and reestablishment of cerebral blood flow. The aim of this narrative review is to elucidate the mechanisms by which MMPs may provide detrimental and/or beneficial effects during the post-stroke injury and repair phases in animal models.

Mkk4 is a negative regulator of the transforming growth factor beta 1 signaling associated with atrial remodeling and arrhythmogenesis with age.

BackgroundAtrial fibrillation (AF), often associated with structural, fibrotic change in cardiac tissues involving regulatory signaling mediators, becomes increasingly common with age. In the present study, we explored the role of mitogen‐activated protein kinase kinase 4 (Mkk4), a critical component of the stress‐activated mitogen‐activated protein kinase family, in age‐associated AF.Methods and ResultsWe developed a novel mouse model with a selective inactivation of atrial cardiomyocyte Mkk4 (Mkk4ACKO). We characterized and compared electrophysiological, histological, and molecular features of young (3‐ to 4‐month), adult (6‐month), and old (1‐year) Mkk4ACKO mice with age‐matched control littermates (Mkk4F/F). Aging Mkk4ACKO mice were more susceptible to atrial tachyarrhythmias than the corresponding Mkk4F/F mice, showing characteristic slow and dispersed atrial conduction, for which modeling studies demonstrated potential arrhythmic effects. These differences paralleled increased interstitial fibrosis, upregulated transforming growth factor beta 1 (TGF‐β1) signaling and dysregulation of matrix metalloproteinases in Mkk4ACKO, compared to Mkk4F/F, atria. Mkk4 inactivation increased the sensitivity of cultured cardiomyocytes to angiotensin II–induced activation of TGF‐β1 signaling. This, in turn, enhanced expression of profibrotic molecules in cultured cardiac fibroblasts, suggesting cross‐talk between these two cell types in profibrotic signaling. Finally, human atrial tissues in AF showed a Mkk4 downregulation associated with increased production of profibrotic molecules, compared to findings in tissue from control subjects in sinus rhythm.ConclusionsThese findings together demonstrate, for the first time, that Mkk4 is a negative regulator of the TGF‐β1 signaling associated with atrial remodeling and arrhythmogenesis with age, establishing Mkk4 as a new potential therapeutic target for treating AF.

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Probes for Non-invasive Matrix Metalloproteinase-targeted Imaging with PET and SPECT

Dysregulation of matrix metalloproteinase (MMP) activity can lead to a wide range of disease states such as atherosclerosis, inflammation or cancer. The ability to image MMP activity non-invasively in vivo, by radiolabelled synthetic inhibitors, would allow the characterization of atherosclerotic plaques, inflammatory lesions or tumors. Here we present an overview of radiolabelled MMP inhibitors (MMPIs) and MMP peptides for positron emission tomography (PET) and single photon emission computed tomography (SPECT) for the detection of proteolytic activity of MMPs. So far, most studies are at a preliminary stage; however, some hydroxamate-based tracers such as the peptidomimetics [¹¹¹In]-DTPA-RP782, [99mTc]-(HYNIC-RP805)(tricine)(TPPTS), or Marimastat-ArB[¹⁸F]F₃ and the picolyl- benzenesulfonamide [¹²³I]I-HO-CGS 27023A identified specifically the enzymatic action of MMPs in animal models of various pathologies. The development of new compounds that may lead to novel tracers (e.g. modification of zinc-binding group, variation of substituents attached to the S1', S2' and S3' pockets of the MMP inhibitors) and the use of antibodies and cell penetrating peptides are also discussed. In general, preclinical studies with atherosclerosis models proved to be more successful than those with oncological models.

The relationship between the first episode of wheezing and matrix metalloproteinases-9 and MMP-2 and tissue inhibitors of MMP-1 levels in preterm infants

AIMS:Matrix metalloproteinases (MMP) have been associated with neonatal lung morbidity and MMP dysregulation contributes to the pathology of chronic and acute lung disorders. Most of the previous studies were performed in the 1st weeks of life of the preterm newborns. There are no data on the serum levels of MMP-2, MMP-9 or tissue inhibitors of matrix metalloproteinases (TIMP-1) from preterm infants recovering from lung morbidities. We aimed to compare MMP-2, MMP-9 and TIMP-1 levels in preterm and term infants hospitalized with their first episode of wheezing.METHODS:We prospectively evaluated 18 preterm infants with a history of chronic lung disease, respiratory distress syndrome or oxygen therapy and 14 age- and sex-matched term infants who were admitted for a first episode of wheezing. We quantified total serum concentrations of MMP-2, MMP-9 and TIMP-1 to assess whether these serum markers levels were associated with the first episode of wheezing in infants with a history of oxygen therapy during the neonatal period.RESULTS:Upon hospitalization, MMP-2 and TIMP-1 levels were higher in preterm infants than in term infants. In contrast, there was no significant relationship between MMP-9 levels or the MMP-9/TIMP-1 ratio between preterm and term infants. The area under the receiver operating characteristic curve for MMP-2 was 0.70 (95% confidence interval [CI] 0.51-0.89). The area under the curve for TIMP-1 was 0.78 (95% CI 0.61-0.94). MMP-9, MMP-2 and TIMP-1 levels did not correlate with gestational age, gender or severity of wheezing.CONCLUSION:The negative proportion of MMP-9 to TIMP-1 that we detected in term infants was not present in preterm infants. The balance of MMP-9 to TIMP-1 may have been disrupted by lung damage in the premature infants. Overproduction of MMP-2 and TIMP-1 in the serum may be associated with the pathogenesis of wheezing in preterm infants.

Lipopolysaccharide regulates MMP-9 expression through TLR4/NF-κB signaling in human arterial smooth muscle cells

Matrix metalloproteinases (MMPs) are critical to vascular smooth muscle cell migration in vivo. The dysregulation of MMPs is involved in the pathogenesis of abnormal arterial remodeling, aneurysm formation and atherosclerotic plaque instability. It has been confirmed that lipopolysaccharides (LPS) constitute a strong risk factor for the development of atherosclerosis. In this study, we aimed to determine a potential mechanism of LPS on MMP-9 expression in human arterial smooth muscle cells (HASMCs). RT-PCR analysis was used to detect MMP-9 mRNA expression and western blot analysis was performed to examine MMP-9 protein expression. An electrophoretic mobility shift assay was also employed to determine NF-κB binding activity. Results showed that LPS induced MMP-9 mRNA and protein expression in HASMCs in a TLR4-dependent manner. Notably, upon blocking the NF-κB binding with pyrrolidine dithiocarbamate, it was demonstrated that the expression of MMP-9 by LPS occurs through TLR4/NF-κB pathways. It was concluded that LPS induced MMP-9 expression through the TLR4/NF-κB pathway. Thus, the TLR4/NF-κB pathway may be involved in the pathogenesis of atherosclerosis.

Cardiomyopathy in the dystrophin/utrophin-deficient mouse model of severe muscular dystrophy is characterized by dysregulation of matrix metalloproteinases

Cardiomyopathy is a significant component in Duchenne muscular dystrophy. Although mdx mice are deficient in dystrophin, they only develop mild indicators of cardiomyopathy before 1year-of-age, making therapeutic investigations using this model lengthy. In contrast, mdx mice also lacking utrophin (utrn(-/-);mdx) show severely reduced cardiac contractile function and histological indicators of cardiomyopathy by 8-10weeks-of-age. Here we demonstrate that utrn(-/-);mdx mice show a similar pattern of cardiac damage to that in dystrophic patients. Matrix metalloproteinases required for ventricular remodeling during the evolution of heart failure are upregulated in utrn(-/-);mdx mice concurrent with the onset of cardiac pathology by 10weeks-of-age. Matrix metalloproteinase activity is further dysregulated due to reduced levels of endogenous tissue inhibitors and co-localizes with fibroblasts and collagen I-containing scars. utrn(-/-);mdx mice are therefore a very useful model for investigating potential cardiac therapies.

Anti-fibrotic cardio protective efficacy of aminoguanidine against streptozotocin induced cardiac fibrosis and high glucose induced collagen up regulation in cardiac fibroblasts

This study mainly focuses on cardio protective anti-fibrotic activity of aminoguanidine against streptozotocin induced cardiac fibrosis and high glucose induced collagen accumulation in cardiac fibroblasts. Dysregulation of matrix metalloproteinase especially 2 and 9 were considered to be responsible for the abnormal collagen deposition, which resulting improper cardiac contractile function in diabetic mice. Mice received a single dose of streptozotocin (100mg/kg) through tail vein to induce diabetes. Normal and diabetic mice received aminoguanidine orally (100mg/kg/day) throughout the study period of 8weeks. Cardiac fibroblasts cultured and exposed to high glucose, aminoguanidine and both for 48h. Collagen quantitatively estimated in both in vivo and in vitro models. Altered structural changes were studied using the Masson tri-chrome staining, TEM images of cardiac sections. Increased collagen and metalloproteinase activities were confirmed using gelatin zymography, western blotting and gene expression studies. The exact mechanism responsible for high glucose induced collagen up regulation in diabetic heart was incompletely understood. From this above in vivo and in vitro results, we conclude that, the cardio protective anti fibrotic activity of amino guanidine was mainly attributed by exhibiting the inhibitory efficacy against streptozotocin and high glucose induced collagen accumulation probably by inhibiting high glucose altered metalloproteinase-2 and -9 activities.

Matrix metalloproteinases in kidney homeostasis and diseases

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that have been increasingly linked to both normal physiology and abnormal pathology in the kidney. Collectively able to degrade all components of the extracellular matrix, MMPs were originally thought to antagonize the development of fibrotic diseases solely through digestion of excessive matrix. However, increasing evidence has shown that MMPs play a wide variety of roles in regulating inflammation, epithelial-mesenchymal transition, cell proliferation, angiogenesis, and apoptosis. We now have robust evidence for MMP dysregulation in a multitude of renal diseases including acute kidney injury, diabetic nephropathy, glomerulonephritis, inherited kidney disease, and chronic allograft nephropathy. The goal of this review is to summarize current findings regarding the role of MMPs in kidney diseases as well as the mechanisms of action of this family of proteases.

Type-specific dysregulation of matrix metalloproteinases and their tissue inhibitors in end-stage heart failure patients: relationship between MMP-10 and LV remodelling

Although past studies observed the changes of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in end-stage heart failure (HF) patients, a consistent and clear pattern of type-specific MMPs and/or TIMPs has yet to be further defined. In this study, proteomic approach of human protein antibody arrays was used to compare MMP and TIMP expression levels of left ventricular (LV) myocardial samples from end-stage HF patients due to dilated cardiomyopathy (DCM) with those from age- and sex- matched non-failing patients. Western blot analysis, immunohistochemistry and ELISA were used for validation of our results. We observed that MMP-10 and -7 abundance increased, accompanied by decreased TIMP-4 in DCM failing hearts (n= 8) compared with non-failing hearts (n= 8). The results were further validated in a cohort of 34 end-stage HF patients derived from three forms of cardiomyopathies. Cardiac and plasma MMP-10 levels were positively correlated with the LV end-diastolic dimension in this HF cohort. In addition, we observed that insulin-like growth factor-2 promoted MMP-10 production in neonatal rat cardiomyocytes. In conclusion, this study demonstrated a selective up-regulation of MMP-10 and -7 along with a discordant change of TIMP-4, and a positive correlation between MMP-10 levels and the degree of LV dilation in end-stage HF patients. Our findings suggest that type-specific dysregulation of MMPs and TIMPs is associated with LV remodelling in end-stage HF patients, and MMP-10 may act as a novel biomarker for LV remodelling.

Exercise training reduces fibrosis and matrix metalloproteinase dysregulation in the aging rat heart

Aging impairs function in the nonischemic heart and is associated with mechanical remodeling. This process includes accumulation of collagen (i.e., fibrosis) and dysregulation of active matrix metalloproteinases (MMPs). Exercise training (ET) improves cardiac function, but the pathways of protection remain poorly understood. Young (3 mo) and old (31 mo) FBNF1 rats were assigned into sedentary and exercise groups, with ET group rats training on a treadmill 45 min/d, 5 d/wk for 12 wk. Nonlinear optical microscopy (NLOM), histology, immunohistochemistry (IHC), and Western blot analyses were performed on the left ventricle and septum. NLOM, IHC, and histological imaging revealed that ET reduced age-associated elevation of collagen type I fibers. Active MMP-1, active MMP-2, and MMP-14 in the ECM fraction of the left ventricle were reduced by aging, an effect abrogated by ET. Tissue inhibitor of MMP (TIMP-1) was elevated with age but protected by ET. Transforming growth factor-β (TGF-β), upstream regulator of TIMP-1, increased with age but was attenuated by ET. Therefore, exercise training could protect the aging heart against dysregulation of MMPs and fibrosis by suppressing elevation of TIMP-1 and TGF-β.

Radiofluorinated Pyrimidine‐2,4,6‐triones as Molecular Probes for Noninvasive MMP‐Targeted Imaging

Matrix metalloproteinases (MMPs) are zinc- and calcium-dependent endopeptidases. Representing a subfamily of the metzincin superfamily, MMPs are involved in the proteolytic degradation of components of the extracellular matrix. Unregulated MMP expression, MMP dysregulation and locally increased MMP activity are common features of various diseases, such as cancer, atherosclerosis, stroke, arthritis, and others. Therefore, activated MMPs are suitable biological targets for the specific visualization of such pathologies, in particular by using radiolabeled MMP inhibitors (MMPIs). The aim of this work was to develop a radiofluorinated molecular probe for noninvasive in vivo imaging for the detection of up-regulated levels of activated MMPs in the living organism. Fluorinated MMPIs (26, 31 and 38) based on the pyrimidine-2,4,6-trione lead structure RO 28-2653 (1) were synthesized, and their MMP inhibition potency was evaluated in vitro. The radiosynthesis and the in vivo biodistribution of the first (18)F-labeled prototype, MMP-targeted tracer [(18)F]26, suitable for molecular imaging by means of positron emission tomography (PET) were realized.

Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy (135.25)

Abstract A third of myocarditis cases progress to dilated cardiomyopathy (DCM); however, the mechanisms controlling this process are largely unknown. Immunization of BALB/c mice with myocarditogenic peptide in CFA adjuvant induced the infiltration of pathogenic IL-17A-secreting T helper type-17 cells into the inflamed heart during the acute stage; and mild-to-severe DCM in the chronic stage of the disease. However, IL-17A deficiency did not abrogate the incidence or severity of myosin-induced myocarditis, nor did it ameliorate the severe disease of IFNγ-deficient mice, suggesting that IL-17A plays a minimal role during acute myocarditis. In contrast, during the chronic stage, IL-17A-deficient mice but not WT littermates were fully protected from the progression to DCM. Flow cytometry and cytokine analysis revealed an important role for IL-17A in the upregulation of IL-6, TNFα, and IL-1β in the heart tissue, and the recruitment of CD11b+ monocytes and Gr1+ granulocytes into the heart. These differences were associated with a significant decrease in myocardial fibrosis and dysregulation of matrix metalloproteinases. Furthermore, neutralization of endogenous IL-17A after the onset of myocarditis decreased myocardial fibrosis and improved systolic function. Our findings reveal a critical role for IL-17A in adverse cardiac remodeling leading to end-stage DCM, and suggest that targeting IL-17A may be an attractive therapeutic strategy for patients with inflammatory DCM.