Ane M. Salvador

Left Ventricular T Cell Recruitment Contributes to the Pathogenesis of Heart Failure

Background—Despite the emerging association between heart failure (HF) and inflammation, the role of T cells, major players in chronic inflammation, has only recently begun to be explored. Whether T-cell recruitment to the left ventricle (LV) participates in the development of HF requires further investigation to identify novel mechanisms that may serve for the design of alternative therapeutic interventions. Methods and Results—Real-time videomicroscopy of T cells from nonischemic HF patients or from mice with HF induced by transverse aortic constriction revealed enhanced adhesion to activated vascular endothelial cells under flow conditions in vitro compared with T cells from healthy subjects or sham mice. T cells in the mediastinal lymph nodes and the intramyocardial endothelium were both activated in response to transverse aortic constriction and the kinetics of LV T-cell infiltration was directly associated with the development of systolic dysfunction. In response to transverse aortic constriction, T cell–deficient mice (T-cell receptor, TCR&agr;−/−) had preserved LV systolic and diastolic function, reduced LV fibrosis, hypertrophy and inflammation, and improved survival compared with wild-type mice. Furthermore, T-cell depletion in wild-type mice after transverse aortic constriction prevented HF. Conclusions—T cells are major contributors to nonischemic HF. Their activation combined with the activation of the LV endothelium results in LV T-cell infiltration negatively contributing to HF progression through mechanisms involving cytokine release and induction of cardiac fibrosis and hypertrophy. Reduction of T-cell infiltration is thus identified as a novel translational target in HF.

Intercellular Adhesion Molecule 1 Regulates Left Ventricular Leukocyte Infiltration, Cardiac Remodeling, and Function in Pressure Overload-Induced Heart Failure.

Background Left ventricular dysfunction and heart failure are strongly associated in humans with increased circulating levels of proinflammatory cytokines, T cells, and soluble intercellular cell adhesion molecule 1 (ICAM1). In mice, infiltration of T cells into the left ventricle contributes to pathological cardiac remodeling, but the mechanisms regulating their recruitment to the heart are unclear. We hypothesized that ICAM1 regulates cardiac inflammation and pathological cardiac remodeling by mediating left ventricular T‐cell recruitment and thus contributing to cardiac dysfunction and heart failure. Methods and Results In a mouse model of pressure overload–induced heart failure, intramyocardial endothelial ICAM1 increased within 48 hours in response to thoracic aortic constriction and remained upregulated as heart failure progressed. ICAM1‐deficient mice had decreased T‐cell and proinflammatory monocyte infiltration in the left ventricle in response to thoracic aortic constriction, despite having numbers of circulating T cells and activated T cells in the heart‐draining lymph nodes that were similar to those of wild‐type mice. ICAM1‐deficient mice did not develop cardiac fibrosis or systolic and diastolic dysfunction in response to thoracic aortic constriction. Exploration of the mechanisms regulating ICAM1 expression revealed that endothelial ICAM1 upregulation and T‐cell infiltration were not mediated by endothelial mineralocorticoid receptor signaling, as demonstrated in thoracic aortic constriction studies in mice with endothelial mineralocorticoid receptor deficiency, but rather were induced by the cardiac cytokines interleukin 1β and 6. Conclusions ICAM1 regulates pathological cardiac remodeling by mediating proinflammatory leukocyte infiltration in the left ventricle and cardiac fibrosis and dysfunction and thus represents a novel target for treatment of heart failure.

CD43 Functions as an E-Selectin Ligand for Th17 Cells In Vitro and Is Required for Rolling on the Vascular Endothelium and Th17 Cell Recruitment during Inflammation In Vivo

Endothelial E- and P-selectins mediate lymphocyte trafficking in inflammatory processes by interacting with lymphocyte selectin ligands. These are differentially expressed among different T cell subsets and function alone or in cooperation to mediate T cell adhesion. In this study, we characterize the expression and functionality of E-selectin ligands in Th type 17 lymphocytes (Th17 cells) and report that CD43 functions as a Th17 cell E-selectin ligand in vitro that mediates Th17 cell rolling on the vascular endothelium and recruitment in vivo. We demonstrate Th17 cells express CD44, P-selectin glycoprotein ligand (PSGL)-1, and CD43. Few PSGL-1−/−CD43−/− Th17 cells accumulated on E-selectin under shear flow conditions compared with wild-type cells. CD43−/− Th17 cell accumulation on E-selectin was impaired as compared with wild-type and PSGL-1−/−, and similar to that observed for PSGL-1−/−CD43−/− Th17 cells, indicating that CD43 alone is a dominant ligand for E-selectin. Notably, this finding is Th17 cell subset specific because CD43 requires cooperation with PSGL-1 in Th1 cells for binding to E-selectin. In vivo, Th17 cell recruitment into the air pouch was reduced in CD43−/− mice in response to CCL20 or TNF-α, and intravital microscopy studies demonstrated that CD43−/− Th17 cells had impaired rolling on TNF-α–treated microvessels. Furthermore, CD43−/− mice were protected from experimental autoimmune encephalomyelitis and had impaired recruitment of Th17 cells in the spinal cord. Our findings demonstrate that CD43 is a major E-selectin ligand in Th17 cells that functions independent of PSGL-1, and they suggest that CD43 may hold promise as a therapeutic target to modulate Th17 cell recruitment.

Th1 effector T cells selectively orchestrate cardiac fibrosis in nonischemic heart failure

Despite emerging data indicating a role for T cells in profibrotic cardiac repair and healing after ischemia, little is known about whether T cells directly impact cardiac fibroblasts (CFBs) to promote cardiac fibrosis (CF) in nonischemic heart failure (HF). Recently, we reported increased T cell infiltration in the fibrotic myocardium of nonischemic HF patients, as well as the protection from CF and HF in TCR-&agr;−/− mice. Here, we report that T cells activated in such a context are mainly IFN-&ggr;+, adhere to CFB, and induce their transition into myofibroblasts. Th1 effector cells selectively drive CF both in vitro and in vivo, whereas adoptive transfer of Th1 cells, opposite to activated IFN-&ggr;−/− Th cells, partially reconstituted CF and HF in TCR-&agr;−/− recipient mice. Mechanistically, Th1 cells use integrin &agr;4 to adhere to and induce TGF-&bgr; in CFB in an IFN-&ggr;–dependent manner. Our findings identify a previously unrecognized role for Th1 cells as integrators of perivascular CF and cardiac dysfunction in nonischemic HF.

Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation

Heart Failure (HF) is associated with increased circulating levels of aldosterone and systemic inflammation. Mineralocorticoid receptor (MR) antagonists block aldosterone action and decrease mortality in patients with congestive HF. However, the molecular mechanisms underlying the therapeutic benefits of MR antagonists remain unclear. MR is expressed in all cell types in the heart, including the endothelial cells (EC), in which aldosterone induces the expression of intercellular adhesion molecule 1 (ICAM‐1). Recently, we reported that ICAM‐1 regulates cardiac inflammation and cardiac function in mice subjected to transverse aortic constriction (TAC). Whether MR specifically in endothelial cells (EC) contributes to the several mechanisms of pathological cardiac remodeling and cardiac dysfunction remains unclear. Basal cardiac function and LV dimensions were comparable in mice with MR selectively deleted from ECs (EC‐MR−/−) and wild‐type littermate controls (EC‐MR+/+). MR was specifically deleted in heart EC, and in EC‐containing tissues, but not in leukocytes of TAC EC‐MR−/− mice. While EC‐MR−/− TAC mice showed preserved systolic function and some alterations in the expression of fetal genes, the proinflammatory cytokine TNFα and the endothelin receptors in the LV as compared to EC‐MR+/+ TAC mice, no difference was observed between both TAC groups in overall cardiac hypertrophy, ICAM‐1 LV expression and leukocyte infiltration, cardiac fibrosis or capillary rarefaction, all hallmarks of pathological cardiac remodeling. Our data indicate that EC‐MR contributes to the transition of cardiac hypertrophy to systolic dysfunction independently of other maladaptive changes induced by LV pressure overload.