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ABSTRACT: Effective postinfarction repair requires timely suppression of innate immune signals to prevent the catastrophic consequences of uncontrolled inflammation on cardiac geometry and function. In macrophages, interleukin-1 receptor-associated kinase (IRAK)-M acts as a functional decoy preventing uncontrolled toll-like receptor /interleukin-1-mediated responses. Our study investigates the role of IRAK-M as a negative regulator of the postinfarction inflammatory response and as a modulator of cardiac remodeling.
In wild-type mouse infarcts IRAK-M was upregulated in infiltrating macrophages and fibroblasts exhibiting a biphasic response. When compared with wild-type animals, infarcted IRAK-M(-/-) mice had enhanced adverse remodeling and worse systolic dysfunction; however, acute infarct size was comparable between groups. Adverse remodeling in IRAK-M(-/-) animals was associated with enhanced myocardial inflammation and protease activation. The protective actions of IRAK-M involved phenotypic modulation of macrophages and fibroblasts. IRAK-M(-/-) infarcts showed increased infiltration with proinflammatory CD11b+/Ly6C(hi) monocytes; leukocytes harvested from IRAK-M-null infarcts exhibited accentuated cytokine expression. In vitro, IRAK-M expression was upregulated in cytokine-stimulated murine cardiac fibroblasts and suppressed their matrix-degrading properties without affecting their inflammatory activity.
Endogenous IRAK-M attenuates adverse postinfarction remodeling suppressing leukocyte inflammatory activity, while inhibiting fibroblast-mediated matrix degradation.
Arteriosclerosis Thrombosis and Vascular Biology 09/2012; 32(11):2598-608. · 6.37 Impact Factor
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ABSTRACT: Cardiac fibroblasts are key cellular effectors of cardiac repair; their phenotype and function are modulated by interactions with extracellular matrix proteins. This review manuscript discusses the effects of the extracellular matrix on the inflammatory and reparative properties of fibroblasts in the infarcted myocardium. Early generation of matrix fragments in the infarct induces a pro-inflammatory and matrix-degrading fibroblast phenotype. Formation of a fibrin/fibronectin-rich provisional matrix serves as a conduit for migration of fibroblasts into the infarcted area. Induction of ED-A fibronectin and nonfibrillar collagens may contribute to myofibroblast transdifferentiation. Upregulation of matricellular proteins promotes transduction of growth factor and cytokine-mediated signals. As the scar matures, matrix cross-linking, clearance of matricellular proteins, and reduced growth factor signaling cause deactivation and apoptosis of reparative infarct fibroblasts. Understanding the effects of matrix components on infarct fibroblasts may guide the design of peptides that reproduce, or inhibit, specific matricellular functions, attenuating adverse remodeling.
Journal of Cardiovascular Translational Research 09/2012; · 2.61 Impact Factor
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ABSTRACT: Fibroblasts are the predominant cell type in the cardiac interstitium. As the main matrix-producing cells in the adult mammalian heart, fibroblasts maintain the integrity of the extracellular matrix network, thus preserving geometry and function. Following myocardial infarction fibroblasts undergo dynamic phenotypic alterations and direct the reparative response. Due to their strategic location, cardiac fibroblasts serve as sentinel cells that sense injury and activate the inflammasome secreting cytokines and chemokines. During the proliferative phase of healing, infarct fibroblasts undergo myofibroblast transdifferentiation forming stress fibers and expressing contractile proteins (such as α-smooth muscle actin). Mechanical stress, transforming growth factor (TGF)-β/Smad3 signaling and alterations in the composition of the extracellular matrix induce acquisition of the myofibroblast phenotype. In the highly cellular and growth factor-rich environment of the infarct, activated myofibroblasts produce matrix proteins, proteases and their inhibitors regulating matrix metabolism. As the infarct matures, "stress-shielding" of myofibroblasts by the cross-linked matrix and growth factor withdrawal may induce quiescence and ultimately cause apoptotic death. Because of their critical role in post-infarction cardiac remodeling, fibroblasts are promising therapeutic targets following myocardial infarction. However, the complexity of fibroblast functions and the pathophysiologic heterogeneity of post-infarction remodeling in the clinical context discourage oversimplified approaches in clinical translation. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.
Biochimica et Biophysica Acta 09/2012; · 4.66 Impact Factor
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ABSTRACT: The matricellular protein thrombospondin (TSP) 1 is induced after tissue injury and may regulate reparative responses by activating transforming growth factor-β, by suppressing angiogenesis and by modulating inflammation and matrix metabolism. We hypothesized that endogenous TSP-1 may be involved in the pathogenesis of cardiac remodeling in the pressure-overloaded heart. Myocardial TSP-1 expression was increased in a mouse model of pressure overload because of transverse aortic constriction. TSP-1(-/-) mice exhibited increased early hypertrophy and enhanced late dilation in response to pressure overload. Pressure-overloaded TSP-1 null mice had intense degenerative cardiomyocyte changes, exhibiting more extensive sarcomeric loss and sarcolemmal disruption when compared with wild-type hearts. Accentuated hypertrophy and cardiomyocyte injury in TSP-1(-/-) hearts was accompanied by increased myofibroblast density. However, despite a 2-fold higher infiltration of the cardiac interstitium with myofibroblasts, pressure-overloaded TSP-1 null hearts did not exhibit significantly increased collagen content when compared with wild-type hearts. The disproportionately low collagen content in TSP-1 null hearts was attributed to infiltration with abundant, but functionally defective, fibroblasts that exhibited impaired myofibroblast differentiation and reduced collagen expression in comparison with wild-type fibroblasts. Impaired myofibroblast activation in TSP-1 null hearts was associated with reduced Smad2 phosphorylation reflecting defective transforming growth factor-β signaling. Moreover, TSP-1 null hearts had increased myocardial matrix metalloproteinase 3 expression and enhanced matrix metalloproteinase 9 activation after pressure overload. TSP-1 upregulation in the pressure-overloaded heart critically regulates fibroblast phenotype and matrix remodeling by activating transforming growth factor-β signaling and by promoting matrix preservation, thus preventing chamber dilation.
Hypertension 09/2011; 58(5):902-11. · 6.21 Impact Factor
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ABSTRACT: Transforming growth factor β (TGF-β) is a central mediator of fibrogenesis. TGF-β is upregulated and activated in fibrotic diseases and modulates fibroblast phenotype and function, inducing myofibroblast transdifferentiation while promoting matrix preservation. Studies in a wide range of experimental models have demonstrated the involvement of the canonical activin receptor-like kinase 5/Smad3 pathway in fibrosis. Smad-independent pathways may regulate Smad activation and, under certain conditions, may directly transduce fibrogenic signals. The profibrotic actions of TGF-β are mediated, at least in part, through induction of its downstream effector, connective tissue growth factor. In light of its essential role in the pathogenesis of fibrosis, TGF-β has emerged as an attractive therapeutic target. However, the pleiotropic and multifunctional effects of TGF-β and its role in tissue homeostasis, immunity and cell proliferation raise concerns regarding potential side effects that may be caused by TGF-β blockade. This minireview summarizes the role of TGF-β signaling pathways in the fibrotic response.
Growth factors (Chur, Switzerland) 07/2011; 29(5):196-202. · 2.47 Impact Factor
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ABSTRACT: The aging heart is characterized by morphological and structural changes that lead to its functional decline and are associated with diminished ability to meet increased demand. Extensive evidence, derived from both clinical and experimental studies suggests that the aging heart undergoes fibrotic remodeling. Age-dependent accumulation of collagen in the heart leads to progressive increase in ventricular stiffness and impaired diastolic function. Increased mechanical load, due to reduced arterial compliance, and direct senescence-associated fibrogenic actions appear to be implicated in the pathogenesis of cardiac fibrosis in the elderly. Evolving evidence suggests that activation of several distinct molecular pathways may contribute to age-related fibrotic cardiac remodeling. Reactive oxygen species, chemokine-mediated recruitment of mononuclear cells and fibroblast progenitors, transforming growth factor (TGF)-β activation, endothelin-1 and angiotensin II signaling mediate interstitial and perivascular fibrosis in the senescent heart. Reduced collagen degradation may be more important than increased de novo synthesis in the pathogenesis of aging-associated fibrosis. In contrast to the baseline activation of fibrogenic pathways in the senescent heart, aging is associated with an impaired reparative response to cardiac injury and defective activation of reparative fibroblasts in response to growth factors. Because these reparative defects result in defective scar formation, senescent hearts are prone to adverse dilative remodeling following myocardial infarction. Understanding the pathogenesis of interstitial fibrosis in the aging heart and dissecting the mechanisms responsible for age-associated healing defects following cardiac injury are critical in order to design new strategies for prevention of adverse remodeling and heart failure in elderly patients.
Aging and disease. 04/2011; 2(2):158-173.
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Nikolaos G Frangogiannis
Circulation 03/2011; 123(12):1267-9. · 14.74 Impact Factor
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Cardiovascular research 11/2010; 89(1):9-11. · 5.80 Impact Factor
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ABSTRACT: Myocardial TGF-β expression is upregulated in experimental models of myocardial infarction and cardiac hypertrophy, and in patients with dilated or hypertrophic cardiomyopathy. Through its effects on cardiomyocytes, mesenchymal and immune cells, TGF-β plays an important role in the pathogenesis of cardiac remodeling and fibrosis. TGF-β overexpression in the mouse heart is associated with fibrosis and hypertrophy. Endogenous TGF-β plays an important role in the pathogenesis of cardiac fibrotic and hypertrophic remodeling, and modulates matrix metabolism in the pressure-overloaded heart. In the infarcted heart, TGF-β deactivates inflammatory macrophages, while promoting myofibroblast transdifferentiation and matrix synthesis through Smad3-dependent pathways. Thus, TGF-β may serve as the "master switchThis article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure". for the transition of the infarct from the inflammatory phase to formation of the scar. Because of its crucial role in cardiac remodeling, the TGF-β system may be a promising therapeutic target for patients with heart failure. However, efforts to translate these concepts into therapeutic strategies, in order to prevent cardiac hypertrophy and fibrosis, are hampered by the complex, pleiotropic and diverse effects of TGF-β signaling, by concerns regarding deleterious actions of TGF-β inhibition and by the possibility of limited benefit in patients receiving optimal treatment with ACE inhibitors and β-adrenergic blockers. Dissection of the pathways responsible for specific TGF-β-mediated actions and understanding of cell-specific actions of TGF-β are needed to design optimal therapeutic strategies. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure".
Journal of Molecular and Cellular Cardiology 11/2010; 51(4):600-6. · 5.17 Impact Factor
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ABSTRACT: Cardiac fibroblasts are key effector cells in the pathogenesis of cardiac fibrosis. Transforming growth factor (TGF)-beta/Smad3 signaling is activated in the border zone of healing infarcts and induces fibrotic remodeling of the infarcted ventricle contributing to the development of diastolic dysfunction.
The present study explores the mechanisms responsible for the fibrogenic effects of Smad3 by dissecting its role in modulating cardiac fibroblast phenotype and function.
Smad3 null mice and corresponding wild-type controls underwent reperfused myocardial infarction protocols. Surprisingly, reduced collagen deposition in Smad3-/- infarcts was associated with increased infiltration with myofibroblasts. In vitro studies demonstrated that TGF-beta1 inhibited murine cardiac fibroblast proliferation; these antiproliferative effects were mediated via Smad3. Smad3-/- fibroblasts were functionally defective, exhibiting impaired collagen lattice contraction when compared with wild-type cells. Decreased contractile function was associated with attenuated TGF-beta-induced expression of alpha-smooth muscle actin. In addition, Smad3-/- fibroblasts had decreased migratory activity on stimulation with serum, and exhibited attenuated TGF-beta1-induced upregulation of extracellular matrix protein synthesis. Upregulation of connective tissue growth factor, an essential downstream mediator in TGF-beta-induced fibrosis, was in part dependent on Smad3. Connective tissue growth factor stimulation enhanced extracellular matrix protein expression by cardiac fibroblasts in a Smad3-independent manner.
Disruption of Smad3 results in infiltration of the infarct with abundant hypofunctional fibroblasts that exhibit impaired myofibroblast transdifferentiation, reduced migratory potential, and suppressed expression of fibrosis-associated genes.
Circulation Research 08/2010; 107(3):418-28. · 9.49 Impact Factor
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ABSTRACT: Myocardial infarction triggers an inflammatory reaction that is involved in cardiac remodeling. Cardiac repair is dependent on regulatory mechanisms that suppress inflammation and prevent excessive matrix degradation. Chemokine induction in the infarcted heart mediates recruitment of leukocyte subsets with distinct properties. We demonstrate that signaling through the CC chemokine receptor 5 (CCR5) prevents uncontrolled postinfarction inflammation and protects from adverse remodeling by recruiting suppressive mononuclear cells. CCR5 and its ligands macrophage inflammatory protein (MIP)-1alpha and MIP-1beta were markedly induced in the infarcted mouse myocardium. In addition, almost 40% of the mononuclear cells infiltrating the infarct expressed CCR5. CCR5(-/-) mice exhibited marked upregulation of proinflammatory cytokine and chemokine expression in the infarct. In wild-type infarcts CCR5+ mononuclear cells had anti-inflammatory properties, expressing higher levels of IL-10 than CCR5- cells. In contrast, mononuclear cells isolated from CCR5(-/-) infarcts had reduced IL-10 expression. Moreover, enhanced inflammation in the absence of CCR5 was associated with impaired recruitment of CD4+/foxp3+ regulatory T cells (Tregs). The CCR5+ Treg subset exhibited increased IL-10 expression, reflecting potent anti-inflammatory activity. Accentuated inflammation in CCR5(-/-) infarcts was associated with increased matrix metalloproteinase (MMP) expression, reduced TIMP levels, and enhanced MMP-2 and MMP-9 activity, resulting in worse cardiac dilation. These results suggest that CCR5-mediated Treg recruitment may restrain postinfarction inflammation, preventing excessive matrix degradation and attenuating adverse remodeling.
American Journal Of Pathology 04/2010; 176(5):2177-87. · 4.89 Impact Factor
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ABSTRACT: Heart failure is strongly associated with aging. Elderly patients with heart failure often have preserved systolic function exhibiting left ventricular hypertrophy accompanied by a decline in diastolic function. Experimental studies have demonstrated that age-related cardiac fibrosis plays an important role in the pathogenesis of diastolic heart failure in senescent hearts. Reactive oxygen species and angiotensin II are critically involved in fibrotic remodeling of the aging ventricle; their fibrogenic actions may be mediated, at least in part, through transforming growth factor (TGF)-beta. The increased prevalence of heart failure in the elderly is also due to impaired responses of the senescent heart to cardiac injury. Aging is associated with suppressed inflammation, delayed phagocytosis of dead cardiomyocytes, and markedly diminished collagen deposition following myocardial infarction, due to a blunted response of fibroblasts to fibrogenic growth factors. Thus, in addition to a baseline activation of fibrogenic pathways, senescent hearts exhibit an impaired reparative reserve due to decreased responses of mesenchymal cells to stimulatory signals. Impaired scar formation in senescent hearts is associated with accentuated dilative remodeling and worse systolic dysfunction. Understanding the pathogenesis of interstitial fibrosis in the aging heart and dissecting the mechanisms responsible for age-associated healing defects following cardiac injury are critical in order to design new strategies for prevention of adverse remodeling and heart failure in elderly patients.
Heart Failure Reviews 03/2010; 15(5):415-22. · 3.20 Impact Factor
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Nikolaos G Frangogiannis
Hypertension 02/2010; 55(2):233-5. · 6.21 Impact Factor
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ABSTRACT: Cardiovascular physiology and pathophysiology vary dramatically over the course of the day. For example, myocardial infarction onset occurs with greater incidence during the early morning hours in humans. However, whether myocardial infarction tolerance exhibits a time-of-day dependence is unknown.
To investigate whether time of day of an ischemic insult influences clinically relevant outcomes in mice.
Wild-type mice were subjected to ischemia/reperfusion (I/R) (45 minutes of ischemia followed by 1 day or 1 month of reperfusion) at distinct times of the day, using the closed-chest left anterior descending coronary artery occlusion model. Following 1 day of reperfusion, hearts subjected to ischemia at the sleep-to-wake transition (zeitgeber time [ZT]12) resulted in 3.5-fold increases in infarct size compared to hearts subjected to ischemia at the wake-to-sleep transition (ZT0). Following 1 month of reperfusion, prior ischemic event at ZT12 versus ZT0 resulted in significantly greater infarct volume, fibrosis, and adverse remodeling, as well as greater depression of contractile function. Genetic ablation of the cardiomyocyte circadian clock (termed cardiomyocyte-specific circadian clock mutant [CCM] mice) attenuated/abolished time-of-day variations in I/R outcomes observed in wild-type hearts. Investigation of Akt and glycogen synthase kinase-3beta in wild-type and CCM hearts identified these kinases as potential mechanistic ties between the cardiomyocyte circadian clock and I/R tolerance.
We expose a profound time-of-day dependence for I/R tolerance, which is mediated by the cardiomyocyte circadian clock. Further understanding of I/R tolerance rhythms will potentially provide novel insight regarding the etiology and treatment of ischemia-induced cardiac dysfunction.
Circulation Research 12/2009; 106(3):546-50. · 9.49 Impact Factor
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ABSTRACT: Interferon-gamma-inducible protein (IP)-10/CXCL10, an angiostatic and antifibrotic chemokine with an important role in T-cell trafficking, is markedly induced in myocardial infarcts, and may regulate the reparative response.
To study the role of IP-10 in cardiac repair and remodeling.
We studied cardiac repair in IP-10-null and wild-type (WT) mice undergoing reperfused infarction protocols and examined the effects of IP-10 on cardiac fibroblast function. IP-10-deficient and WT animals had comparable acute infarct size. However, the absence of IP-10 resulted in a hypercellular early reparative response and delayed contraction of the scar. Infarcted IP-10(-/-) hearts exhibited accentuated early dilation, followed by rapid wall thinning during infarct maturation associated with systolic dysfunction. Although IP-10-null and WT mice had comparable cytokine expression, the absence of IP-10 was associated with marked alterations in the cellular content of the infarct. IP-10(-/-) infarcts had more intense infiltration with CD45(+) leukocytes, Mac-2(+) macrophages, and alpha-smooth muscle actin (alpha-SMA)(+) myofibroblasts than WT infarcts but exhibited reduced recruitment of the subpopulations of leukocytes, T lymphocytes and alpha-SMA(+) cells that expressed CXCR3, the IP-10 receptor. IP-10 did not modulate cardiac fibroblast proliferation and apoptosis but significantly inhibited basic fibroblast growth factor-induced fibroblast migration. In addition, IP-10 enhanced growth factor-mediated wound contraction in fibroblast-populated collagen lattices.
Endogenous IP-10 is an essential inhibitory signal that regulates the cellular composition of the healing infarct and promotes wound contraction, attenuating adverse remodeling. IP-10-mediated actions may be due, at least in part, to direct effects on fibroblast migration and function.
Circulation Research 09/2009; 105(10):973-83. · 9.49 Impact Factor
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ABSTRACT: The dynamic alterations in the cardiac extracellular matrix following myocardial infarction not only determine the mechanical properties of the infarcted heart, but also directly modulate the inflammatory and reparative response. During the inflammatory phase of healing, rapid activation of Matrix Metalloproteinases (MMP) causes degradation of the cardiac extracellular matrix. Matrix fragments exert potent pro-inflammatory actions, while MMPs process cytokines and chemokines altering their biological activity. In addition, vascular hyperpermeability results in extravasation of fibronectin and fibrinogen leading to formation of a plasma-derived provisional matrix that serves as a scaffold for leukocyte infiltration. Clearance of the infarct from dead cells and matrix debris is essential for resolution of inflammation and marks the transition to the proliferative phase. The fibrin-based provisional matrix is lysed and cellular fibronectin is secreted. ED-A fibronectin, mechanical tension and Transforming Growth Factor (TGF)-beta are essential for modulation of fibroblasts into myofibroblasts, the main collagen-secreting cells in the wound. The matricellular proteins thrombospondin-1 and -2, osteopontin, tenascin-C, periostin, and secreted protein acidic and rich in cysteine (SPARC) are induced in the infarct regulating cellular interactions and promoting matrix organization. As the infarct matures, matrix cross-linking results in formation of a dense collagen-based scar. At this stage, shielding of fibroblasts from external mechanical tension by the mature matrix network may promote deactivation and cellular quiescence. The components of the extracellular matrix do not passively follow the pathologic alterations of the infarcted heart but critically modulate inflammatory and reparative pathways by transducing signals that affect cell survival, phenotype and gene expression.
Journal of Molecular and Cellular Cardiology 08/2009; 48(3):504-11. · 5.17 Impact Factor
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ABSTRACT: The CC chemokine monocyte chemoattractant protein (MCP)-1/CCL2 is involved in the formation, progression, and destabilization of atheromatous plaques and plays an essential role in postinfarction remodeling. These properties generated significant interest in the potential significance of MCP-1 as a biomarker in acute coronary syndromes (ACS). Emerging evidence suggests that MCP-1 plasma levels have prognostic value in the acute and chronic phase following ACS, providing information independent of standard clinical variables. The mechanisms responsible for adverse prognosis in patients with elevated plasma MCP-1 following ACS remain unknown. High plasma MCP-1 levels may reflect a higher burden of atherosclerotic disease, may exert prothrombotic effects resulting in recurrent coronary events, or may identify patients who mount a more intense cardiac inflammatory reaction following a coronary event, resulting in enhanced adverse remodeling. Beyond its prognostic significance, the MCP-1 axis may be an attractive target for therapy in patients with ACS.
Current Atherosclerosis Reports 04/2009; 11(2):131-8. · 2.66 Impact Factor
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ABSTRACT: Obesity and diabetes are frequently associated with cardiovascular disease. When a normal heart is subjected to brief/sublethal repetitive ischemia and reperfusion (I/R), adaptive responses are activated to preserve cardiac structure and function. These responses include but are not limited to alterations in cardiac metabolism, reduced calcium responsiveness, and induction of antioxidant enzymes. In a model of ischemic cardiomyopathy inducible by brief repetitive I/R, we hypothesized that dysregulation of these adaptive responses in diet-induced obese (DIO) mice would contribute to enhanced myocardial injury. DIO C57BL/6J mice were subjected to 15 min of daily repetitive I/R while under short-acting anesthesia, a protocol that results in the development of fibrotic cardiomyopathy. Cardiac lipids and candidate gene expression were analyzed at 3 days, and histology at 5 days of repetitive I/R. Total free fatty acids (FFAs) in the cardiac extracts of DIO mice were significantly elevated, reflecting primarily the dietary fatty acid (FA) composition. Compared with lean controls, cardiac FA oxidation (FAO) capacity of DIO mice was significantly higher, concurrent with increased expression of FA metabolism gene transcripts. Following 15 min of daily repetitive I/R for 3 or 5 days, DIO mice exhibited increased susceptibility to I/R and, in contrast to lean mice, developed microinfarction, which was associated with an exaggerated inflammatory response. Repetitive I/R in DIO mice was associated with more profound significant downregulation of FA metabolism gene transcripts and elevated FFAs and triglycerides. Maladaptive metabolic changes of FA metabolism contribute to enhanced myocardial injury in diet-induced obesity.
Obesity 11/2008; 16(12):2593-600. · 4.28 Impact Factor
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ABSTRACT: The proinflammatory cytokine interleukin (IL)-1 signals exclusively through the type I IL-1 receptor (IL-1RI). IL-1 expression is markedly induced in the infarcted heart; however, its role in cardiac injury and repair remains controversial. We examined the effects of disrupted IL-1 signaling on infarct healing and cardiac remodeling using IL-1RI(-/-) mice. After reperfused infarction IL-1RI-null mice exhibited decreased infiltration of the infarcted myocardium with neutrophils and macrophages and reduced chemokine and cytokine expression. In the absence of IL-1 signaling, suppressed inflammation was followed by an attenuated fibrotic response. Infarcted IL-1RI(-/-) mice had decreased myofibroblast infiltration and reduced collagen deposition in the infarcted and remodeling myocardium. IL-1RI deficiency protected against the development of adverse remodeling; however, infarct size was comparable between groups suggesting that the beneficial effects of IL-1RI gene disruption were not attributable to decreased cardiomyocyte injury. Reduced chamber dilation in IL-1RI-null animals was associated with decreased collagen deposition and attenuated matrix metalloproteinase (MMP)-2 and MMP-3 expression in the peri-infarct area, suggesting decreased fibrotic remodeling of the noninfarcted heart. IL-1beta stimulated MMP mRNA synthesis in wild-type, but not in IL-1RI-null cardiac fibroblasts. In conclusion, IL-1 signaling is essential for activation of inflammatory and fibrogenic pathways in the healing infarct, playing an important role in the pathogenesis of remodeling after infarction. Thus, interventional therapeutics targeting the IL-1 system may have great benefits in myocardial infarction.
American Journal Of Pathology 08/2008; 173(1):57-67. · 4.89 Impact Factor
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Nikolaos G Frangogiannis
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ABSTRACT: Myocardial infarction is the most common cause of cardiac injury and results in acute loss of a large number of myocardial cells. Because the heart has negligible regenerative capacity, cardiomyocyte death triggers a reparative response that ultimately results in formation of a scar and is associated with dilative remodeling of the ventricle. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Toll-like receptor-mediated pathways, the complement cascade and reactive oxygen generation induce nuclear factor (NF)-kappaB activation and upregulate chemokine and cytokine synthesis in the infarcted heart. Chemokines stimulate the chemotactic recruitment of inflammatory leukocytes into the infarct, while cytokines promote adhesive interactions between leukocytes and endothelial cells, resulting in transmigration of inflammatory cells into the site of injury. Monocyte subsets play distinct roles in phagocytosis of dead cardiomyocytes and in granulation tissue formation through the release of growth factors. Clearance of dead cells and matrix debris may be essential for resolution of inflammation and transition into the reparative phase. Transforming growth factor (TGF)-beta plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. Myofibroblast proliferation and angiogenesis result in formation of highly vascularized granulation tissue. As the healing infarct matures, fibroblasts become apoptotic and a collagen-based matrix is formed, while many infarct neovessels acquire a muscular coat and uncoated vessels regress. Timely resolution of the inflammatory infiltrate and spatial containment of the inflammatory and reparative response into the infarcted area are essential for optimal infarct healing. Targeting inflammatory pathways following infarction may reduce cardiomyocyte injury and attenuate adverse remodeling. In addition, understanding the role of the immune system in cardiac repair is necessary in order to design optimal strategies for cardiac regeneration.
Pharmacological Research 07/2008; 58(2):88-111. · 4.44 Impact Factor
