Atherosclerosis is a chronic inflammatory arterial disease characterized by focal accumulation of lipid and inflammatory cells. It is the number one cause of deaths in the Western world because of its complications of heart attacks and strokes. Statins are effective in only approximately one third of patients, underscoring the urgent need for additional therapies. B cells that accumulate in atherosclerotic lesions and the aortic adventitia of humans and mice are considered to protect against atherosclerosis development. Unexpectedly, we found that selective B cell depletion in apolipoprotein E-deficient (ApoE−/−) mice using a well-characterized mAb to mouse CD20 reduced atherosclerosis development and progression without affecting the hyperlipidemia imposed by a high-fat diet. Adoptive transfer of 5 × 106 or 5 × 107 conventional B2 B cells but not 5 × 106 B1 B cells to a lymphocyte-deficient ApoE−/− Rag-2−/− common cytokine receptor γ-chain–deficient mouse that was fed a high-fat diet augmented atherosclerosis by 72%. Transfer of 5 × 106 B2 B cells to an ApoE−/− mouse deficient only in B cells aggravated atherosclerosis by >300%. Our findings provide compelling evidence for the hitherto unrecognized proatherogenic role of conventional B2 cells. The data indicate that B2 cells can potently promote atherosclerosis development entirely on their own in the total absence of all other lymphocyte populations. Additionally, these B2 cells can also significantly augment atherosclerosis development in the presence of T cells and all other lymphocyte populations. Our findings raise the prospect of B cell depletion as a therapeutic approach to inhibit atherosclerosis development and progression in humans.

Background— Heart attacks and strokes, leading causes of deaths globally, arise from thrombotic occlusion of ruptured vulnerable atherosclerotic plaques characterized by abundant apoptosis, large necrotic cores derived from inefficient apoptotic cell clearance, thin fibrous caps, and focal inflammation. The genesis of apoptosis and necrotic cores in these vulnerable atherosclerotic plaques remains unknown. Cytotoxic CD8 + T lymphocytes represent up to 50% of leukocytes in advanced human plaques and dominate early immune responses in mouse lesions, yet their role in atherosclerosis also remains unresolved. Methods and Results— CD8 + T-lymphocyte depletion by CD8α or CD8β monoclonal antibody in apolipoprotein E-deficient mice fed a high-fat diet ameliorated atherosclerosis by reducing lipid and macrophage accumulation, apoptosis, necrotic cores, and monocyte chemoattractant protein 1, interleukin 1β, interferon γ, and vascular cell adhesion molecule 1. Transfer of CD8 + T cells into lymphocyte-deficient, apolipoprotein E-deficient mice partially reconstituted CD8 + T cells in lymphoid compartments and was associated with CD8 + T-cell infiltration in lesions, increased lipid and macrophage accumulation, apoptotic cells, necrotic cores, and interleukin 1β in atherosclerotic lesions. Transfer of CD8 + T cells deficient in perforin, granzyme B, or tumor necrosis factor α but not interferon γ failed to increase atherosclerotic lesions despite partial reconstitution in the lymphoid system and the presence in atherosclerotic lesions. Macrophages, smooth muscle cells, and endothelial cells were identified as apoptotic targets. Conclusions— We conclude that CD8 + T lymphocytes promote the development of vulnerable atherosclerotic plaques by perforin- and granzyme B–mediated apoptosis of macrophages, smooth muscle cells, and endothelial cells that, in turn, leads to necrotic core formation and further augments inflammation by tumor necrosis factor α secretion.

The mechanism by which FO B cells promote atherosclerosis is highly dependent on their expression of MHCII, CD40, and Blimp-1. FO B cell differentiation into IgG-producing plasma cells also is critical for their proatherogenic actions. Targeting B-T cell interactions and pathogenic IgG may provide novel therapeutic strategies to prevent atherosclerosis and its adverse cardiovascular complications.

This data indicates that the antihypertrophic actions of ANP are accompanied by reduced levels of superoxide, suggesting an antioxidant action contributes to the antihypertrophic actions of ANP.

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The objective was a comprehensive investigation of the mechanisms and sites of resveratrol cardioprotection during and following ischemia-reperfusion (I-R) injury, and to determine whether direct preservation of cardiomyocytes is an important site of cardioprotection. We now provide the first definitive evidence that resveratrol specifically protects cardiomyocytes from I-R injury via a combination of suppression of superoxide levels and activation of potassium channels. This protection is apparent whether resveratrol is present for the full duration of the insult or only on recovery. In addition, resveratrol improved postischemic recovery of left ventricular contractile function, attenuated myocardial injury, and increased myocardial activation of the survival kinase Akt in the intact heart. Furthermore, resveratrol elicited direct concentration-dependent protective actions on the vasculature (vasorelaxation, superoxide suppression) and enhanced endothelium-dependent vasodilatation. Resveratrol thus targets a number of consequences of myocardial I-R, including release of reactive oxygen species, loss of recovery of contractile function, and impaired endothelium-dependent vasodilatation. Previous evidence indicates that resveratrol elicits potent preconditioning in the heart. Given that myocardial ischemic events are often unpredictable in humans, the findings that resveratrol protection is also evident when administered during and/or after the insult adds new dimensions to the clinical potential of resveratrol.

BACKGROUND AND PURPOSEAnnexin-A1 (ANX-A1) is an endogenous, glucocorticoid-regulated anti-inflammatory protein. The N-terminal-derived peptide Ac-ANX-A12-26 preserves cardiomyocyte viability, but the impact of ANX-A1-peptides on cardiac contractility is unknown. We now test the hypothesis that ANX-A1 preserves post-ischaemic recovery of left ventricular (LV) function. EXPERIMENTAL APPROACHAc-ANX-A12-26 was administered on reperfusion, to adult rat cardiomyocytes as well as hearts isolated from rats, wild-type mice and mice deficient in endogenous ANX-A1 (ANX-A1 -/-). Myocardial viability and recovery of LV function were determined. KEY RESULTSIschaemia-reperfusion markedly impaired both cardiomyocyte viability and recovery of LV function by 60%. Treatment with exogenous Ac-ANX-A12-26 at the onset of reperfusion prevented cardiomyocyte injury and significantly improved recovery of LV function, in both intact rat and wild-type mouse hearts. Ac-ANX-A12-26 cardioprotection was abolished by either formyl peptide receptor (FPR)-nonselective or FPR1-selective antagonists, Boc2 and cyclosporin H, but was relatively insensitive to the FPR2-selective antagonist QuinC7. ANX-A1-induced cardioprotection was associated with increased phosphorylation of the cell survival kinase Akt. ANX-A1-/-exaggerated impairment of post-ischaemic recovery of LV function, in addition to selective LV FPR1 down-regulation. CONCLUSIONS AND IMPLICATIONSThese data represent the first evidence that ANX-A1 affects myocardial function. Our findings suggest ANX-A1 is an endogenous regulator of post-ischaemic recovery of LV function. Furthermore, the ANX-A1-derived peptide Ac-ANX-A12-26 on reperfusion rescues LV function, probably via activation of FPR1. ANX-A1-based therapies may thus represent a novel clinical approach for the prevention and treatment of myocardial reperfusion injury.

We conclude that TNF-α produced by B2 cells is a key mechanism by which B2 cells promote atherogenesis through augmenting macrophage TNF-α production to induce cell death and inflammation that promote plaque vulnerability.