Key result
In a mouse model of heart failure after myocardial infarction, AT1R blockade with telmisartan or myeloid cell depletion attenuated endothelial dysfunction and vascular accumulation of Nox2+ myeloid cells.
Why the study?
Heart failure following myocardial infarction triggers systemic inflammation, but the impact of myelomonocytic cells and their activation by angiotensin II on vascular endothelial function remained unclear.
Does myeloid cell depletion or AT1R blockade with telmisartan improve vascular endothelial function in a mouse model of heart failure after myocardial infarction?
Does myeloid cell depletion or AT1R blockade with telmisartan improve vascular endothelial function in a mouse model of heart failure after myocardial infarction?
In a mouse model of heart failure after MI, endothelial dysfunction is driven by inflammatory Nox2+ myeloid cells and can be mitigated by AT1R blockade with telmisartan.
Telmisartan or myeloid depletion attenuates post-MI endothelial dysfunction in mice; hypothesis-generating for AT1R-targeted vascular therapies in human heart failure.
AIMS: Heart failure (HF) ensuing myocardial infarction (MI) is characterized by the initiation of a systemic inflammatory response. We aimed to elucidate the impact of myelomonocytic cells and their activation by angiotensin II on vascular endothelial function in a mouse model of HF after MI. METHODS AND RESULTS: HF was induced in male C57BL/6J mice by permanent ligation of the left anterior descending coronary artery. Compared to sham, HF mice had significantly impaired endothelial function accompanied by enhanced mobilization of Sca-1+c-Kit+ haematopoietic stem cells and Sca-1-c-Kit+ common myeloid and granulocyte-macrophage progenitors in the bone marrow as well as increased vascular infiltration of CD11b+Ly6G-Ly6Chigh monocytes and accumulation of CD11b+ F4/80+ macrophages, assessed by flow cytometry. Using mice with Cre-inducible expression of diphtheria toxin receptor in myeloid cells, we selectively depleted lysozyme M+ myelomonocytic cells for 10 days starting 28 days after MI. While the cardiac phenotype remained unaltered until 38 days post-MI, myeloid cell depletion attenuated vascular accumulation of Nox2+CD45+ cells, endothelial dysfunction, oxidative stress, and vascular expression of adhesion molecules and angiotensin II receptor type 1 (AT1R). Pharmacological blockade of this receptor for 4 weeks did not significantly alter cardiac function, but mimicked the effects of myeloid cell depletion: telmisartan (20 mg/kg/day, fed to C57BL/6J mice) diminished bone marrow myelopoesis and myeloid reactive oxygen species production, attenuated endothelial leucocyte rolling and vascular accumulation of CD11b+Ly6G-Ly6Chigh monocytes and macrophages, resulting in improved vascular function with less abundance of Nox2+CD45+ cells. CONCLUSION: Endothelial dysfunction in HF ensuing MI is mediated by inflammatory Nox2+ myeloid cells infiltrating the vessel wall that can be targeted by AT1R blockade.
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Molitor et al. (2020) studied Heart failure after myocardial infarction. Myeloid cell depletion or telmisartan vs. Sham was evaluated on Vascular endothelial function and inflammation. In a mouse model of heart failure after myocardial infarction, AT1R blockade with telmisartan or myeloid cell depletion attenuated endothelial dysfunction and vascular accumulation of Nox2+ myeloid cells.
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