Background:
Left ventricular (LV) dysfunction and Heart Failure (HF) are associated in humans with systemic inflammation, including increased circulating levels of pro-inflammatory cytokines and soluble intercellular cell adhesion molecule-1 (ICAM-1). Endothelial ICAM-1 regulates leukocyte recruitment into tissues, which in the heart can result in altered cardiac function. We
hypothesize
that ICAM-1 regulates cardiac remodeling by mediating leukocyte recruitment to the LV and thus contributing to worsening of cardiac function during pressure overload induced HF.
Methods and results:
We used the mouse model of Thoracic Aortic Constriction (TAC) to induce LV remodeling and HF in WT and ICAM-1 deficient mice (ICAM-1
-/-
). Immunohistochemistry, flow cytometry, qPCR, echocardiography and hemodynamics were used to investigate leukocyte infiltration into the LV, cardiac function, hypertrophy and fibrosis mechanisms taking place in response to TAC. Endothelial ICAM-1 was upregulated in WT mice in response to TAC as compared to Sham, correlating with LV T cell infiltration. In contrast, CD3+ and CD4+ T cell recruitment into the LV was significantly reduced in response to TAC in ICAM-1
-/-
mice as compared to WT mice. Further, indices of sistolic and diastolic function were preserved in ICAM-1
-/-
mice (dP/dt
max
= WT TAC 5,627±549 vs. ICAM-1
-/-
TAC 8,396±1,495 ; dP/dt
min
= WT TAC -5,614±1,195 vs. ICAM-
1-/-
TAC -8,832±2,274) and the End Diastolic Pressure was significantly lower than in WT TAC mice (31.0±7.0mmHg in WT TAC vs 8.1±7.8mmHg in ICAM-1
-/-
TAC). Despite increased LV weight, ICAM-1
-/-
did not develop fibrosis in response to TAC, with blunted collagen deposition and lack of mRNA upregulation of fibrotic markers Collagen-I, TGFβ and SMAα four and ten weeks after TAC when dilated cardiomiopathy is established in WT mice.
Conclusion:
Our data indicate that ICAM-1 regulates LV T cell infiltration, cardiac function and fibrosis in HF induced by TAC. Further studies will determine whether ICAM-1 contributes to HF pathogenesis exclusively by regulating T cell interactions with the LV endothelium or participating in novel mechanisms regulating cardiac cell function, which could represent new targets for the treatment of this deadly syndrome.
Dendritic cell recruitment in response to skin antigen tests in HIV-1-infected individuals correlates with the level of T-cell infiltration
