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Ngkelo et al. use a mast cell–deficient mouse model to reveal a protective role of mast cells in myocardial infarction, through regulation of the cardiac contractile machinery.

Altogether, our data demonstrate that regulation of proangiogenic Ly6C(hi) monocytes systemic levels by CCL2/CCR2 controls post-ischaemic vessel growth, whereas Ly6C(lo) monocytes have no major role in this setting.

Objective-Leukocyte infiltration in ischemic areas is a hallmark of myocardial infarction, and overwhelming infiltration of innate immune cells has been shown to promote adverse remodeling and cardiac rupture. Recruitment of inflammatory cells in the ischemic heart depends highly on the family of CC-chemokines and their receptors. Here, we hypothesized that the chemokine decoy receptor D6, which specifically binds and scavenges inflammatory CC-chemokines, might limit inflammation and adverse cardiac remodeling after infarction. Methods and Results-D6 was expressed in human and murine infarcted myocardium. In a murine model of myocardial infarction, D6 deficiency led to increased chemokine (C-C motif) ligand 2 and chemokine (C-C motif) ligand 3 levels in the ischemic heart. D6-deficient (D6 −/− ) infarcts displayed increased infiltration of pathogenic neutrophils and Ly6Chi monocytes, associated with strong matrix metalloproteinase-9 and matrix metalloproteinase-2 activities in the ischemic heart. D6 −/− mice were cardiac rupture prone after myocardial infarction, and functional analysis revealed that D6 −/− hearts had features of adverse remodeling with left ventricle dilation and reduced ejection fraction. Bone marrow chimera experiments showed that leukocyte-borne D6 had no role in this setting, and that leukocyte-specific chemokine (C-C motif) receptor 2 deficiency rescued the adverse phenotype observed in D6 −/− mice. Conclusion-We show for the first time that the chemokine decoy receptor D6 limits CC-chemokine-dependent pathogenic inflammation and is required for adequate cardiac remodeling after myocardial infarction.

Background— Interaction with heparan sulfate proteoglycans is supposed to provide chemokines with the capacity to immobilize on cell surface and extracellular matrix for accomplishing both tissue homing and signaling of attracted cells. However, the consequences of the exclusive invalidation of such interaction on the roles played by endogenous chemokines in vivo remain unascertained. Methods and Results— We engineered a mouse carrying a Cxcl12 gene ( Cxcl12 Gagtm ) mutation that precludes interactions with heparan sulfate structures while not affecting CXCR4-dependent cell signaling of CXCL12 isoforms (α, β, γ). Cxcl12 Gagtm/Gagtm mice develop normally, express normal levels of total and isoform-specific Cxcl12 mRNA, and show increased counting of circulating CD34 + hematopoietic precursor cells. After induced acute ischemia, a marked impaired capacity to support revascularization was observed in Cxcl12 Gagtm/Gagtm animals associated with a reduced number of infiltrating cells in the ischemic tissue despite the massive expression of CXCL12 isoforms. Importantly, exogenous administration of CXCL12γ, which binds heparan sulfate with the highest affinity ever reported for a cytokine, fully restores vascular growth, whereas heparan sulfate–binding CXCL12γ mutants failed to promote revascularization in Cxcl12 Gagtm/Gagtm animals. Conclusion— These findings prove the role played by heparan sulfate interactions in the functions of CXCL12 in both homeostasis and physiopathological settings and document for the first time the paradigm of chemokine immobilization in vivo.

Protecting the heart after an acute coronary syndrome is a key therapeutic goal to support cardiac recovery and prevent progression to heart failure. A potential strategy is to target cardiac glucose metabolism at the early stages after ischemia when glycolysis is critical for myocyte survival. Building on our discovery that high-density lipoprotein (HDL) modulates skeletal muscle glucose metabolism, we now demonstrate that a single dose of reconstituted HDL (rHDL) delivered after myocardial ischemia increases cardiac glucose uptake, reduces infarct size, and improves cardiac remodeling in association with enhanced functional recovery in mice. These findings applied equally to metabolically normal and insulin-resistant mice. We further establish direct effects of HDL on cardiomyocyte glucose uptake, glycolysis, and glucose oxidation via the Akt signaling pathway within 15 min of reperfusion. These data support the use of infusible HDL preparations for management of acute coronary syndromes in the setting of primary percutaneous interventions.

Objective-Catecholamines have been shown to control bone marrow (BM)-derived cell egress, yet the cellular and molecular mechanisms involved in this effect and their subsequent participation to postischemic vessel growth are poorly understood. Methods and Results-Tyrosine hydroxylase mRNA levels, as well as dopamine (DA) and norepinephrine (NE) contents, were increased in the ischemic BM of mice with right femoral artery ligation. Angiographic score, capillary density, and arteriole number were markedly increased by treatments with DA (IP, 50 mg/kg, 5 days) or NE (IP, 2.5 mg/kg, 5 days). Using chimeric mice lethally irradiated and transplanted with BM-derived cells from green fluorescent protein mice, we showed that DA and NE enhanced by 70% (PϽ0.01) and 62% (PϽ0.001), respectively, the number of green fluorescent protein-positive BM-derived cells in ischemic tissue and promoted their ability to differentiate into cells with endothelial and inflammatory phenotypes. Similarly, both DA and NE increased the in vitro differentiation of cultured BM-derived cells into cells with endothelial phenotype. This increase was blunted by the nitric oxide synthase inhibitor N -nitro-L-arginine methyl ester. DA and NE also upregulated the number of CD45-positive cells in blood 3 days after ischemia and that of macrophages in ischemic tissue 21 days after ischemia. Of interest, DA and NE increased BM endothelial nitric oxide synthase (eNOS) mRNA levels and were unable to promote BM-derived cell mobilization in chimeric eNOS-deficient mice lethally irradiated and transplanted with BM-derived cells from wild-type animals. Furthermore, administration of a ␤2 adrenergic agonist (clenbuterol, IP, 2 mg/kg, 5 days) and that of a dopaminergic D1/D5 receptor agonist (SKF-38393, IP, 2.5 mg/kg, 5 days) also enhanced BM-derived cell mobilization and subsequently postischemic vessel growth. Key Words: angiogenesis Ⅲ catecholamines Ⅲ ischemia Ⅲ nitric oxide Ⅲ nitric oxide synthase M obilization and recruitment of bone marrow (BM)-derived cells are of paramount importance and occupy a predominant hierarchical role in the orchestration of tissue remodeling after ischemia. Progenitor cells maintenance and mobilization in the BM are controlled by various cytokines, including colony-stimulating factors and angiogenic cytokines 1 and involve activation of proteinases, such as elastase, cathepsin G, and the matrix metalloproteinases (MMPs). Among them, MMP-9 upregulation results in the release of soluble Kit-ligand expressed by stromal cells and in the activation of BM progenitor cells motility and mobilization. 2 Furthermore, MMP-9 was demonstrated to be essential for vascular endothelial growth factor (VEGF)-induced, CXCL12-induced, and placenta growth factor-induced progenitor cell mobilization. It is also known that BM-derived endothelial nitric oxide synthase (eNOS) is a substantial component of the stem cell niche and is required for the mobilization of BM-derived progenitor cells [3][4][5] Of interest, eNOS-deficient mice show a profoundly re...

Rationale: Decades of research have examined immune modulatory strategies to protect the heart after an acute myocardial infarction and prevent progression to heart failure, but have failed to translate to clinical benefit. Objective: To determine anti-inflammatory actions of apoA-I nanoparticles (n-apoA-I) that contribute to cardiac tissue recovery after myocardial infarction. Methods and Results: Using a preclinical mouse model of myocardial infarction, we demonstrate that a single intravenous bolus of n-apoA-I (CSL111, 80mg/kg) delivered immediately after reperfusion, reduced the systemic and cardiac inflammatory response. N-apoA-I treatment lowered the number of circulating leukocytes by 30{plus minus}7% and their recruitment into the ischemic heart by 25{plus minus}10% (all p<5.0E-2). This was associated with a reduction in plasma levels of the clinical biomarker of cardiac injury, cardiac troponin-I by 52{plus minus}17% (p=1.01E-2). N-apoA-I reduced the cardiac expression of chemokines that attract neutrophils and monocytes by 60-80%, and lowered surface expression of integrin CD11b on monocytes by 20{plus minus}5% (all p<5.0E-2). Fluorescently labeled n-apoA-I entered the infarct and peri-infarct regions and co-localized with cardiomyocytes undergoing apoptosis and with leukocytes. We further demonstrate that n-apoA-I binds to neutrophils and monocytes, with preferential binding to the pro-inflammatory monocyte subtype and partially via scavenger receptor BI (SR-BI). In patients with type 2 diabetes mellitus, we also observed that intravenous infusion of the same n-apoA-I (CSL111, 80mg/kg) similarly reduced the level of circulating leukocytes by 12{plus minus}5% (all p<5.0E-2). Conclusions: A single intravenous bolus of n-apoA-I delivered immediately post-myocardial infarction reduced the systemic and cardiac inflammatory response through direct actions on both the ischemic myocardium and leukocytes. These data highlight the anti-inflammatory effects of n-apoA-I and provide preclinical support for investigation of its use for management of acute coronary syndromes in the setting of primary percutaneous coronary interventions.