Immune Cell and Other Noncardiomyocyte Regulation of Cardiac Hypertrophy and Remodeling
2015; Lippincott Williams & Wilkins; Volume: 131; Issue: 11 Linguagem: Inglês
10.1161/circulationaha.114.008788
ISSN1524-4539
AutoresRyan A. Frieler, Richard M. Mortensen,
Tópico(s)Macrophage Migration Inhibitory Factor
ResumoHomeCirculationVol. 131, No. 11Immune Cell and Other Noncardiomyocyte Regulation of Cardiac Hypertrophy and Remodeling Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBImmune Cell and Other Noncardiomyocyte Regulation of Cardiac Hypertrophy and Remodeling Ryan A. Frieler, PhD and Richard M. Mortensen, MD, PhD Ryan A. FrielerRyan A. Frieler From Department of Molecular and Integrative Physiology (R.A.F., R.M.M.), Department of Internal Medicine, Metabolism, Endocrinology, and Diabetes Division (R.M.M.), and Department of Pharmacology (R.M.M.), University of Michigan Medical School, Ann Arbor. and Richard M. MortensenRichard M. Mortensen From Department of Molecular and Integrative Physiology (R.A.F., R.M.M.), Department of Internal Medicine, Metabolism, Endocrinology, and Diabetes Division (R.M.M.), and Department of Pharmacology (R.M.M.), University of Michigan Medical School, Ann Arbor. Originally published17 Mar 2015https://doi.org/10.1161/CIRCULATIONAHA.114.008788Circulation. 2015;131:1019–1030Cardiac hypertrophy and remodeling are pathological features of many cardiac diseases, with underlying causes including hypertension, cardiomyopathy, valvular dysfunction, and myocardial infarction. In these diseases, ventricular hypertrophy occurs in response to pathological stimuli such as pressure and volume overload, sarcomere gene mutations, and neurohumoral activation, and a major consequence of prolonged and uncontrolled hypertrophic remodeling is cardiac dysfunction, which can lead to heart failure or cardiac arrest resulting from arrhythmia.Despite the various pathological stimuli, there are many common features in the hypertrophic response in different cardiac diseases. In addition to increased cardiomyocyte mass, sarcomere rearrangement, and extracellular matrix deposition, other common features have recently been appreciated, including inflammatory signaling and immune cell activation. Numerous cell types are involved in orchestrating this complex pathological response. The heart consists of a heterogeneous population of cells, including cardiomyocytes and noncardiomyocytes, and it is now clear that intercellular signaling and communication between these cell types are critical in the pathophysiology of ventricular hypertrophy and remodeling (Figure 1).Download figureDownload PowerPointFigure 1. Overview of cardiomyocyte and noncardiomyocyte interactions during cardiac hypertrophy and remodeling. Cardiomyocytes respond to pathogenic stimuli by secreting inflammatory cytokines, chemokines, and damage-associated molecular pattern molecules (DAMPs), which are recognized by local noncardiomyocyte cells. This induces activation and expansion of resident macrophages and fibroblasts and recruits bone marrow–derived immune cells from the circulation. Activated immune cells and fibroblasts secrete both prohypertrophic and profibrotic cytokines, which induce cardiomyocyte hypertrophy and promote fibroblast differentiation, matrix deposition, and interstitial fibrosis. ECM indicates extracellular matrix.Noncardiomyocytes display phenotypic changes during the development of cardiac hypertrophy. There is still much to be revealed about the specific roles of these cell types and their overall contribution to the hypertrophic response. Inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and transforming growth factor-β (TGF-β) and neurohumoral factors such as angiotensin II and aldosterone are involved in the pathophysiology and correlate with disease progression, but the cell type–specific targets and their effects on the cardiomyocyte in vivo are not well understood. The influence of both resident and infiltrating immune cells during myocardial infarction and postinfarction remodeling is well recognized. Recently, it has been shown that myeloid cell phenotypes play a critical role in ventricular hypertrophy and remodeling.1,2 In addition, there is a small body of literature examining specific immune cell interactions in other models of ventricular hypertrophy such as pressure overload. Although the early phases of myocardial infarction are dissimilar to the pathophysiology of progressive, chronic hypertrophy, studies focusing on the later phase of postinfarct hypertrophic remodeling may provide some insight into potential cellular mechanisms and therapeutic targets.In this review, we summarize the current understanding of the role of noncardiomyocytes in the pathogenesis of cardiac hypertrophy, placing particular emphasis on relevant immune cell interactions and inflammatory signaling mechanisms. We highlight seminal findings demonstrating the importance of specific cell types in regulating the cardiomyocyte hypertrophic response, and we emphasize the relevant current and potential therapeutic targets. It is clear that this field is not fully developed and deserves increased attention.Renin-Angiotensin-Aldosterone System and TGF-β Signaling in the Hypertrophic HeartActivation of the renin-angiotensin-aldosterone system (RAAS) has direct hypertensive effects that contribute to cardiac hypertrophy and remodeling, and these effects can be blocked by RAAS inhibition with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor (MR) antagonists. RAAS inhibitors are widely used in the treatment of heart failure and significantly reduce morbidity and mortality; however, it is now well established that these protective effects extend beyond simply reducing blood pressure. Angiotensin II and aldosterone promote vascular and cardiac fibrosis and hypertrophy independently of blood pressure, and these signaling pathways have been shown to have pathogenic effects involving numerous cell types, including cardiomyocytes and immune cells.The role of angiotensin II in both normal and pathological contexts is very complex. Cardiomyocytes express both angiotensin II type 1 and 2 receptors, and both appear to have an important but opposite role in maladaptive remodeling. In bone marrow–derived cells, angiotensin II type I receptors are involved in angiotensin II–induced hypertensive responses,3 and angiotensin II type 1 receptor has also been shown to regulate the mobilization of monocyte progenitor cells.4 Angiotensin II type 1 receptor responses may also be critical in regulating lymphocyte hypertensive responses.5 Our understanding of the many cell-specific effects is still undeveloped, but it is clear that localized, nonclassic RAAS activation is an important target for RAAS inhibitors and a potential mechanism for their beneficial effects.In the past decade, there has been increasing interest in the direct role of MR activation during pathological remodeling. In severe heart failure, clinical trials have demonstrated that MR antagonism provides significant benefit independently of blood pressure lowering.6 MR is expressed in a wide range of cells, and the use of cell-specific knockout technology has now delineated some of the cell-specific effects. Both cardiomyocyte MR and myeloid MR have now been shown to directly influence cardiac remodeling.2,7,8TGF-β is upregulated in the hypertrophied and fibrotic heart and is regarded as one of the major profibrotic cytokines and critical mediators of cardiac fibrosis. TGF-β has many pleiotropic effects in modulating cardiomyocyte and noncardiomyocyte function, and it induces cardiomyocyte hypertrophy and fibroblast proliferation and fibrosis. Inhibition of TGF-β signaling and genetic ablation of TGF-β have been shown to reduce fibrosis and to prevent cardiac dysfunction in several models of maladaptive cardiac remodeling,9,10 whereas TGF-β overexpression has been shown to induce cardiac hypertrophy.11In pressure overload–induced cardiac remodeling, Koitabashi et al12 found that TGF-β–neutralizing antibody reduced myocardial fibrosis without affecting hypertrophy or cardiac function. They further revealed that cardiomyocyte-specific (Myh6-Cre) knockout of TGF-β receptor type II, but not type I, significantly reduced hypertrophy and fibrosis and prevented cardiac dysfunction through a TGF-β–activated kinase 1 signaling pathway. In fact, TGF-β–activated kinase 1 activation is known to induce cardiac hypertrophy; therefore, the TGF-β–TGF-β–activated kinase 1 signaling pathway may be useful for therapeutic targeting.13 However, different TGF-β signaling pathways are context dependent because knockout of both cardiomyocyte TGF-β receptors 1 and 2 significantly ameliorated postinfarct cardiac remodeling.14 Global blockade of TGF-β with neutralizing antibody, on the other hand, resulted in complete mortality within 5 days, suggesting that TGF-β has many diverse effects in specific cell types. In addition to highlighting the importance of specific TGF-β signaling mechanisms, this may indicate that TGF-β is necessary in other target cells for proper regulation of adaptive remodeling.Inflammatory Signaling in Hypertrophic RemodelingInflammatory signaling molecules released during cardiac injury and hypertrophic remodeling can induce hypertrophic and fibrotic responses. Both cardiomyocyte and noncardiomyocyte cells secrete and respond to numerous cytokines, but the responses are complex, depend on the cell type, and are mostly characterized in vitro (Figure 2).Download figureDownload PowerPointFigure 2. Detailed hypertrophic and fibrotic signaling mechanisms between cardiac cells. Interactions between cardiac cells involve complex signaling pathways that induce phenotypic changes in nearby cells. Hypertrophy and fibrosis can be augmented by proinflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin [IL]-1β, IL-6) and profibrotic and molecules (transforming growth factor-β [TGF-β], angiotensin [Ang] II). Renin-angiotensin-aldosterone system activation has direct proinflammatory, prohypertrophic, and profibrotic effects in cardiac cells, and these responses are pharmacologically inhibited with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor (MR) antagonists. Regulatory T cells (Tregs) and exogenous IL-10 treatment can also suppress inflammation and hypertrophic signaling. AT1 indicates angiotensin II type 1; DAMPs, damage-associated molecular pattern molecules; IFN-γ, interferon-γ; MCP, monocyte chemoattractant protein; MMP, matrix metalloproteinase; PAR-2, protease-activated receptor 2; PDGF-A, platelet-derived growth factor-A; rhIL, recombinant human interleukin; ROS, reactive oxygen species; Th1, T helper cell type 1; and TLR, Toll-like receptor.In fibroblasts, major proinflammatory cytokines such as IL-1β, TNF-α, and IL-6 inhibit proliferation, decrease matrix synthesis, and increase MMP activity. In cardiomyocytes, they induce hypertrophy and can cause apoptosis, and in immune cells, they promote inflammation.15–18 However, the cell sources of the cytokines have usually not been identified, and even the target cells of the cytokines have not been fully defined in vivo. The complexity is further increased by the temporal changes that occur in the injury and immune responses, leading to an incomplete understanding of these cytokines during disease.In patients with heart failure, the concentration of the inflammatory cytokines TNF-α, IL-6, and IL-1β correlates with disease severity.19 Experimental models have shown that infusion with TNF-α induces cardiac dysfunction20 and similarly that cardiomyocyte-restricted overexpression of TNF-α induces cardiac hypertrophy and fibrosis and leads to cardiac dysfunction and dilated cardiomyopathy.21 In contrast, global knockout of TNF-α ameliorates pressure overload–induced cardiac hypertrophy, fibrosis, and cardiac dysfunction.22 Anti–TNF-α therapies are also beneficial in animal models, but to a lesser extent. Neutralization of TNF-α significantly blocked TNF-α–induced cardiac inflammation without affecting hypertrophy and producing minor decreases in cardiac dysfunction.23 Although TNF-α causes cardiac dysfunction and TNF-α inhibition ameliorates cardiac dysfunction in animal models, clinical studies have demonstrated that TNF-α inhibition with etanercept and infliximab had no benefit in chronic heart failure.24,25IL-1β–deficient mice have reduced pressure overload–induced hypertrophy and cardiac dysfunction, suggesting that IL-1β has an exacerbating role in hypertrophic remodeling.26 In agreement with this, IL-1β injections were shown to induce cardiac dysfunction in mice.27 During heart failure, early clinical studies indicate that blocking IL-1β signaling provides a significant health benefit. Patients who received the IL-1 receptor antagonist anakinra had increased oxygen consumption and exercise performance.27 These results are promising, although larger trials that assess cardiac function and remodeling are needed. In other pathologies, anakinra has been shown to reduce adverse cardiac remodeling. In patients with rheumatoid arthritis, treatment with anakinra reduced IL-6, C-reactive protein, and endothelin and significantly improved left ventricular function.28 Similarly, patients with acute myocardial infarction with ST-segment elevation who received anakinra had a reduction in C-reactive protein, and treatment blocked the progression to heart failure.29IL-6 has many pleiotropic effects on cardiomyocytes and noncardiomyocytes, and IL-6 infusion alone has been shown to induce cardiac hypertrophy, fibrosis, and diastolic dysfunction.30 In support of having a detrimental role during cardiac hypertrophy, genetic deletion of IL-6 has been shown to ameliorate cardiac damage and to suppress angiotensin II–induced cardiac hypertrophy, fibrosis, and inflammation, as well as hypertrophic and fibrotic signaling.31,32 IL-6 knockout has also been shown to prevent norepinephrine-induced hypertrophy and remodeling.33 However, our understanding of the IL-6 signaling cascade remains incomplete. Knockout of IL-6 in other hypertrophic disease models such as pressure overload has no effect on hypertrophy or fibrosis, and deletion of GP130, part of the IL-6 receptor complex, actually increases mortality after pressure overload and impairs cardiac function, leading to dilated cardiomyopathy.34 It is clear that our understanding of the IL-6 signaling pathways is inadequate within the context of these different disease models and requires further exploration.Anti-Inflammatory SignalingInactivation of proinflammatory responses has been shown to mitigate hypertrophic cardiac dysfunction and remodeling; therefore, it is not surprising that many studies have targeted anti-inflammatory signaling pathways as a therapeutic strategy. IL-10 is a major anti-inflammatory cytokine, and IL-10–deficient mice have increased angiotensin II–induced vascular inflammation and impaired vascular relaxation, indicating that IL-10 has a protective role in maintaining vascular function.35 Another study demonstrated that IL-10–deficient mice had increased cardiac hypertrophy and fibrosis and increased cardiac dysfunction in response to isoproterenol.36 During pressure overload, IL-10–deficient mice had increased perivascular fibrosis but no differences in cardiac hypertrophy or cardiac function.37 However, administration of IL-10 significantly reduced cardiac hypertrophy and fibrosis and preserved cardiac function in both pressure-overload and isoproterenol models of cardiac hypertrophy.36Glucocorticoids have major anti-inflammatory and immunosuppressive effects and are among the most widely used and most effective anti-inflammatory therapeutic agents. Despite their highly potent anti-inflammatory effects, their utility in cardiovascular diseases is limited by a lack of efficacy in the treatment of hypertrophic remodeling. However, it appears that glucocorticoid receptors may have an important role in normal cardiac development and function because cardiomyocyte-specific (Myh6-Cre) glucocorticoid receptor knockout causes cardiac hypertrophy and impaired cardiac function, leading to heart failure and premature death.38Immune CellsIt is now evident that resident and recruited immune cells respond much earlier to cardiac injury than previously thought. These changes precede hypertrophy and remodeling and persist throughout much of the major maladaptive hypertrophic response, resulting in cardiac dysfunction and failure. Immune cells coordinate cardiomyocyte and noncardiomyocyte responses during maladaptive remodeling, and the regulation of immune cell phenotypes represents an important pharmacological approach. These cells have critical roles in not only cardiomyocyte function but also injury responses involving scar formation and interstitial fibrosis, which affect cardiac function.Cardiac MacrophagesThe heart contains a heterogeneous population of macrophages that are present in both healthy and injured cardiac tissue in both humans and mice.39 Similar to tissue macrophages in brain and liver, most macrophages in the heart are established embryonically from yolk sac and fetal liver progenitors, and resident macrophage subsets are maintained through local proliferation and, to a lesser extent, monocyte recruitment.40,41 This is consistent with other recent findings demonstrating that in the absence of disease, most tissue macrophage populations are maintained locally though self-renewal.42 In the presence of tissue injury, monocyte-derived macrophages are much more prevalent.During cardiac injury, the phagocytic function of the macrophage is critical for clearance of necrotic debris and matrix remodeling. However, the function of cardiac macrophages is much more extensive than previously thought, and they have a much more substantial role in regulating cardiac hypertrophy and remodeling. During myocardial infarction or angiotensin II infusion, expansion of macrophage populations occurs through both local proliferation and monocyte recruitment.40 Consistent with a potential causal role, expansion of cardiac macrophage populations occurred as early as 2 days after angiotensin II infusion and before significant hypertrophy and fibrosis occur.40 This suggests that during progressive cardiac hypertrophy and remodeling, inflammatory changes are occurring very early and precede hypertrophic remodeling.Epelman and colleagues40 recently identified 4 distinct macrophage subsets in the mouse heart that have unique functional roles. All characterized subsets were capable of phagocytizing antigen and cardiomyocytes, and MHC-IIhi subsets were capable of antigen presentation and T-cell activation. During angiotensin II infusion, the CCR2+, CD11chi subset was derived predominantly from circulating monocytes and had robust inflammasome activation and inflammatory gene expression. Angiotensin II–induced inflammasome activation and IL-1β production were blocked by C-C chemokine receptor 2 (CCR2) deficiency, suggesting that the CCR2+ subset has a more predominant role in coordinating inflammation. In contrast, other cardiac tissue macrophage subsets probably function as sentinel immune cells and have roles in tissue surveillance, phagocytosis of dying cardiomyocytes, response to cardiomyocyte signaling, and T-cell activation.Macrophage DepletionInhibition or depletion of specific immune cell types has provided some insight into their roles in hypertrophic remodeling (Table 1). Macrophage depletion studies using clodronate liposomes or CD11b-DTR transgenic mice have been performed in a wide range of pathologies to block inflammation. Depletion of macrophages in a hypertensive model with Ren-2 rats suggests that macrophages are necessary for cardiac repair. Although no differences in cardiac hypertrophy were observed, depletion with clodronate liposomes resulted in cardiac dysfunction with decreased ejection fraction and fractional shortening and increased end-diastolic volume.43 Greater cardiomyocyte loss and abundant increases in CD4+ T cells were present in macrophage-depleted rats, suggesting that macrophages are important in coordinating T-cell responses.Table 1. Depletion or Inhibition of Immune Cells During Cardiac Hypertrophy and RemodelingCell TypeTreatmentModelFunctionHypertrophyFibrosisInflammationBPReferenceMonocyte/macrophage/phagocytic cellsClodronate liposomesRen2 rats↓NE↓Mp, ↓Mo, ↑TlNE43Clodronate liposomesAng II↓↓Mp, ↓TNF-α, ↓TGF-β44BM-CCR2−/−Ang IINENE↓↓MpNE45, 46Anti-MCP1AAC↑NE↓↓Mp, ↓TGF-β47MCP1−/−Ang IINENE↓↓Mp,NE44, 48LysM-iDTRAng II↑↓ (PV)↓Mp, ↑Np↓49T lymphocyteAnti-CD3CM–TNF-α Tg↓↓Tl, ↑CD11b+50Rag2−/−TAC↑↓↓Mp51Rag1−/−TACNENE↑ (PV)37Rag1−/−Ang II↑↓52CD8−/−, anti-CD8Ang IINE↓↓TNF-α, ↓TGF-βNE44CD8−/−TACNENE51APCsMHCII−/−TAC↑↓↓Mp51Mast cellsDeficient, cKit mutantAAC↑↓↓NE53Deficient, cKit mutantCM–TNF-α Tg↑↓↓↓TGF-β54Deficient, cKit mutantTACNE, ↓AFNE↓55Mast cell stabilizerAV fistula↑↓56Mast cell stabilizerSHRNENE↓↑IL-10, ↑IL-6NE57LeukocytesICAM-I−/−AACNE↓↓Mp, ↓TGF-βNE58AAC indicates abdominal aortic constriction; AF, atrial fibrillation; Ang II, angiotensin II; APC, antigen-presenting cell; AV, arteriovenous; BM, bone marrow; BP, blood pressure; CM, cardiomyocyte; ICAM-I, intracellular adhesion molecule-1; IL, interleukin; MCP1, monocyte chemoattractant protein 1; Mo, monocyte; Mp, macrophage; NE, no effect; Np, neutrophil; PV, perivascular; SHR, spontaneously hypertensive rat; TAC, transverse aortic constriction; Tg, transgenic; TGF-β, transforming growth factor-β; Tl, T lymphocyte; and TNF-α, tumor necrosis factor-α.During myocardial infarction, macrophage depletion also impairs postinfarction remodeling and repair.59–61 Macrophage depletion during the early inflammatory phase resulted in increased necrotic debris and neutrophil presence, whereas depletion during the later remodeling phase prevented collagen deposition and granulation tissue formation. Because different subsets of cardiac macrophages have different functional roles and because depletion of macrophages with clodronate liposomes is nonselective and depletes all macrophage subsets and peripheral monocytes, it is understandable that macrophage depletion would prevent important reparative functions. In addition, timing of macrophage depletion and targeting of specific macrophage subsets may be critical in achieving effective amelioration of maladaptive remodeling.Inhibition of Monocyte TraffickingThe CCR2+ macrophage subset is monocyte derived and is thought to be involved mainly in promoting and regulating inflammation. Therefore, targeting inflammatory monocytes might be an effective means to limit this macrophage subset. Recruitment of monocytes occurs largely through monocyte chemoattractant protein 1 (MCP1)–CCR2 signaling, and CCR2 knockout in bone marrow cells markedly reduces angiotensin II–induced vascular inflammation and fibrosis without affecting hypertrophy.45 Similarly, inhibition of MCP1 with neutralizing antibodies significantly reduces macrophage infiltration and prevents myocardial fibrosis in response to pressure overload.47 Although there were no differences in cardiac hypertrophy, MCP1 neutralization restored diastolic function.MCP1 knockout is also protective against angiotensin II–induced hypertrophic remodeling. MCP1 knockout mice exhibited suppressed inflammatory cytokine production and reduced fibrosis during early time points, but by 6 weeks, the inflammatory and profibrotic changes normalized, and no differences in hypertrophy or cardiac function were present.48 This suggests that blocking monocytes by targeting the MCP1-CCR2 signaling pathway may be a useful strategy to reduce CCR2+ inflammatory macrophage subsets while maintaining other resident populations carrying out sentinel, phagocytic, and remodeling functions. Blocking this chemotactic pathway appears to have a greater impact on fibrotic remodeling and might have a more direct role in regulating fibroblast function. Because many of the targeting strategies are time dependent, a more thorough characterization of the functional phenotypes at various pathophysiological stages will be necessary.Different Macrophage Phenotypes and PolarizationMacrophages display a range of functionally heterogeneous phenotypes, and a major focus of research has been an understanding of the roles of different macrophage phenotypes during disease. Modulating specific immune cell phenotypes to ameliorate disease is an enticing strategy and could be an important therapeutic approach (Table 2).Table 2. Modulation or Enhancement of Immune Cells in Cardiac Hypertrophy and RemodelingCell TypeTreatmentModelFunctionHypertrophyFibrosisInflammationBPReferenceBM/myeloid cells, modulatorsMR KOL-NAME/Ang II↓↓↓Mp, ↓TNF-α, ↓TGF-βNE2PHD2 KOL-NAME/Ang II↑↓↓↓Mp, ↓TGF-βNE62BM-PI3K-KD (inactive)TAC↑NE↓↓CD18+, ↓TGF-β63BM-mi155 KOAng II↑↓↓CD45+ leukocytesNE1T lymphocytes, enhancementTreg adoptive transferAng II↓↓↓Mp, ↓Tl, ↓TNF-αNE64Treg adoptive transferTAC↓↓↓Mp, ↓Tl, ↓TGF-βNE65Treg adoptive transferAng II↓TNF-α, ↓IFN-γ, ↓IL-6↓66Treg-CVB3-H310A1CM–TNF-α Tg↓↓CD11b+, ↑IL-10, ↑Treg50Ang II indicates angiotensin II; BM, bone marrow–derived; BP, blood pressure; CM, cardiomyocyte; IFN-γ, interferon-γ; IL, interleukin; KO, knockout; L-NAME, l-NG-nitroarginine methyl ester; Mp, macrophage; MR, mineralocorticoid receptor; NE, no effect; PHD2, prolyl hydroxylase domain protein 2; PI3K-KD, kinase-dead phosphatidylinositol 3-kinase; TAC, transverse aortic constriction; Tg, transgenic; TGF-β, transforming growth factor-β; Tl, T lymphocyte; TNF-α, tumor necrosis factor-α; and Treg, regulatory T lymphocyte.In contrast to depleting or blocking macrophage responses, manipulation of the macrophage phenotypes may provide a novel way to prevent specific deleterious inflammatory effects while still allowing other critical phagocytic and reparative responses.Macrophages are capable of integrating a wide array of environmental signals and can respond through unique activation programs. Although initially designated M1 (classic) and M2 (alternative) on the basis of activation by T helper cell type 1 (Th1)– and type 2 (Th2)–mediated cytokines, macrophage activation falls within a spectrum of classically activated macrophage and alternatively activated macrophage (AAM) phenotypes.AAMs are thought to have beneficial, wound-healing effects in many cardiovascular diseases and are one of the major macrophage subsets in the healthy heart.40,67 During myocardial infarction, the predominance of different macrophage phenotypes is phase dependent. During the initially inflammatory phase, there is an increase in classically activated macrophages, whereas during the later remodeling phase, AAMs predominate.68 Little is known about the functional macrophage phenotypes during the development of pressure overload and angiotensin II–induced hypertrophic remodeling.Regulation of Hypertrophic Remodeling by Macrophage and Myeloid PhenotypeAlthough our understanding of the roles for AAM phenotypes in cardiovascular diseases is limited, several studies have demonstrated that these phenotypes correlate with cardiovascular protection. Through the use of cell type–specific targeting and knowledge of specific signaling effectors that regulate macrophage activation, it is now possible to delineate the roles of specific macrophage phenotypes during cardiac hypertrophy. Although comprehensive data are lacking, numerous regulators of macrophage activation have been identified, and several studies have shown that modulation of the myeloid phenotype can regulate the hypertrophic and fibrotic response.MR is a regulator of macrophage polarization, and activation by mineralocorticoids enhances proinflammatory classically activated macrophage phenotypes, whereas MR antagonists and MR knockout suppress the inflammatory response and skew macrophages toward an AAM phenotype.2 Importantly, myeloid-specific deletion of MR significantly reduced l-NG-nitroarginine methyl ester (L-NAME)/angiotensin II–induced cardiac hypertrophy and fibrosis. Conditional myeloid MR knockout using LysM-Cre resulted in the suppression of inflammatory genes and increased expression of AAM markers in cardiac tissue. This suggests that myeloid cell modulation may be an important mechanism for the beneficial effects of MR antagonists used clinically to treat heart failure and post–myocardial infarction patients. Myeloid MR has also been shown to be important in stroke and may have important roles in other cardiovascular diseases.69Hypoxia-inducible factor has important regulatory effects in myeloid cells, and hypoxia-inducible factor activation may be a critical regulator of myeloid phenotype during cardiac remodeling. A recent study demonstrated that myeloid-specific deletion (LysM-Cre) of prolyl hydroxylase domain protein 2, which hydroxylates and induces degradation of hypoxia-inducible factors, attenuates L-NAME/angiotensin II–induced cardiac remodeling.62 Myeloid prolyl hydroxylase domain protein 2 knockout mice had reduced cardiac hypertrophy and fibrosis, decreased macrophage recruitment and inflammatory gene expression, and preserved cardiac function. Prolyl hydroxylase domain protein 2–deficient macrophages were shown to have reduced expression of classically activated macrophage markers and increased expression of the AAM marker Arg1, suggesting that regulation of macrophage polarization could be a potential mechanism of cardioprotection.Phosphatidylinositol 3-kinase (PI3K) is a downstream effector of many different signaling pathways, including certain Toll-like receptors and cytokine receptors, and studies have implicated PI3K signaling in cardiac pathophysiology. Insulin-like growth factor-1 has been shown to induce cardiac hypertrophy through a PI3K-dependent pathway.70 A study using a kinase-dead PI3K (PI3K KD) found that PI3K inactivation
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