Intercellular Adhesion Molecule 1 Regulates Left Ventricular Leukocyte Recruitment, Cardiac Remodeling and Function in Pressure Overload Induced Heart Failure
Authors: Salvador Ane Miren , Nevers Tania , Aronovitz Mark , Wang Bonnie , Jaffe Iris , Blanton Robert , Alcaide Pilar 
Published: November 2023

Left ventricular (LV) dysfunction and Heart Failure (HF) are strongly associated in humans with high circulating levels of pro‐inflammatory cytokines, T cells, soluble intercellular cell adhesion molecule‐1 (ICAM‐1) and aldosterone, a hormone that can induce endothelial ICAM‐1. We previously found that LV T cell recruitment contributes to pathological cardiac remodeling and HF, but the mechanisms mediating cardiac T cell recruitment are poorly understood. We hypothesized that upregulation of cardiac endothelial ICAM‐1 in response to pressure overload results in LV T cell recruitment and cardiac dysfunction in HF. We used the mouse model of Thoracic Aortic Constriction (TAC) to induce LV remodeling and HF in WT, ICAM‐1 deficient mice (ICAM‐1−/−) and endothelial cell specific mineralocorticoid receptor deficient mice (EC‐MR−/−), and the Langendorff perfusion apparatus for adult mouse CM isolation. Immunohistochemistry, flow cytometry, qPCR, echocardiography and hemodynamics were used to measure: leukocyte infiltration into the LV, cardiac hypertrophy, fibrosis and function. Endothelial ICAM‐1 was upregulated in WT mice as compared to Sham as early as 48 hours after TAC, together with IL‐1β and IL‐6, known endothelial cell activators. ICAM‐1 remained upregulated as HF progressed, correlating with LV T cell and Ly6Chigh monocyte infiltration, and LV upregulation of the T cell chemoattractants CXCL9, CXCL10 and CXCL11. This process appears to be independent of endothelial cell‐MR, since EC‐MR−/− mice had upregulated ICAM‐1 and increased cardiac inflammation and leukocyte recruitment similar to EC‐MR+/+ littermates in response to TAC. In contrast, T cell and Ly6Chigh pro‐inflammatory monocyte recruitment into the LV was significantly reduced in response to TAC in ICAM‐1−/− mice. Interestingly, T cells were similarly activated in the heart draining lymph nodes and in blood in similar frequencies in both WT and ICAM‐1−/− mice after TAC. Despite LV weight increased to the same extent in WT and ICAM‐1−/− mice in response to TAC, ICAM‐1−/− mice did not develop fibrosis in response to TAC. ICAM‐1−/− bone marrow derived monocytes differentiated towards M2‐pro‐fibrotic macrophages in vitro similarly to WT monocytes. Moreover, ICAM‐1−/− mice had preserved systolic and diastolic function (dP/dtmax = WT TAC 5,627±549 vs. ICAM‐1−/− TAC 8,396±1,495; dP/dtmin = WT TAC ‐5,614±1,195 vs. ICAM‐1−/− TAC ‐8,832±2,274; End Diastolic Pressure = WT TAC mice 31.0±7.0mmHg vs 8.1±7.8mmHg in ICAM‐1−/−TAC). Our data indicate that endothelial ICAM‐1 is induced in response to TAC independently of EC‐MR signaling, and mediates LV inflammatory leukocyte infiltration, cardiac fibrosis and cardiac dysfunction. Further studies will determine whether ICAM‐1 contributes to HF pathogenesis exclusively by regulating T cell interactions with the LV endothelium or by participating in novel mechanisms regulating CM function, which could represent new targets for the treatment of heart failure.

Support or Funding Information

NIH T32 HL69770 (Dr. Nevers)

NIH 1KL2TR001063‐01 (Dr. Blanton)

K99‐HL097406, NIH‐RO1‐HL123658, AHA GIA 13GRNT 14560068 (Dr. Alcaide)