Abstract 263: Inhibition of Angiotensin II Signaling on LysM+ Myelomonocytic Cells and Their Depletion Improves Vascular Endothelial Dysfunction in Mice With Heart Failure After Myocardial Infarction

2018 ◽  
Vol 38 (Suppl_1) ◽  
Author(s):  
Wolf-Stephan Rudi
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Vascular Endothelial ◽  
Vascular Endothelial Dysfunction ◽  
Angiotensin Ii Signaling ◽  
Myelomonocytic Cells

Nox2+ myeloid cells drive vascular inflammation and endothelial dysfunction in heart failure after myocardial infarction via angiotensin II receptor type 1

2020 ◽  
Author(s):  
Michael Molitor ◽  
Wolf-Stephan Rudi ◽  
Venkata Garlapati ◽  
Stefanie Finger ◽  
Rebecca Schüler ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Bone Marrow ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Angiotensin Ii Receptor ◽  
Myelomonocytic Cells

Abstract 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.

Nox2+ myeloid cells drive vascular inflammation and endothelial dysfunction in heart failure after myocardial infarction via angiotensin II receptor type 1

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Molitor ◽  
W.S Rudi ◽  
V.S Garlapati ◽  
S Finger ◽  
J Wild ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Bone Marrow ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Angiotensin Ii Receptor ◽  
Myelomonocytic Cells

Abstract Background Ischemic heart failure (HF) ensuing myocardial infarction (MI) leads to impaired left ventricular function, reduced cardiac output and counterregulatory activation of angiotensin II (AngII) levels. Furthermore, it is characterized by the initiation of a systemic inflammatory response. Objective 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. 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+ hematopoietic 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 d starting 28d after MI. While the cardiac phenotype remained unaltered until 38d 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/d, fed to C57BL/6J mice) diminished bone marrow myelopoesis and myeloid ROS production, attenuated endothelial leukocyte 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. Funding Acknowledgement Type of funding source: None

Abstract 212: Role of Monocytes and Inflammation in Vascular Endothelial Dysfunction in Mice With Heart Failure After Myocardial Infarction

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Michael Molitor ◽  
Stefanie Finger ◽  
Sabine Kossmann ◽  
Venkata S Garlapati ◽  
Jérémy Lagrange ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Muscle Function ◽  
Diphtheria Toxin ◽  
Vascular Dysfunction ◽  
Aortic Tissue ◽  
Vascular Endothelial ◽  
Smooth Muscle Function ◽  
Myelomonocytic Cells

Background: Heart failure (HF) after myocardial infarction (MI) leads to impaired left ventricular function and reduced blood flow in peripheral arteries. Angiotensin II (ATII) signaling is crucial in MI, and inflammatory myelomonocytic cells are involved in the process of ATII-induced vascular dysfunction. Their role in MI-mediated vascular dysfunction has not been defined yet. Objective: Test the impact of selective depletion of lysozyme M positive (LysM+) myelomonocytic cells on endothelial dysfunction in a model of ischemic heart failure in mice Methods and results: 8 to 12 week old mice (C57B6 background) were subjected to permanent coronary ligation of the left anterior descending artery (LAD) to induced HF post MI. We measured a reduced vascular endothelial and smooth muscle function in isolated aortic segments 7d and 28d post MI in isometric tension studies. Also the production of vascular superoxide (chemiluminescence, oxidative fluorescence microtopography) and vascular mRNA expression of MCP-1, VCAM-1, IL-6 and ATII receptor type 1 were increased (assessed by mRNA reverse transcription polymerase chain reaction) in HF mice compared to sham. FACS analysis of aortic tissue of HF mice shows an increased infiltration of CD45+ immune cells in the aortic wall, including CD11b+Gr-1lowF4/80+ monocytes/macrophages. Using mice with LysM dependent cre-inducible expression of diphtheria toxin receptor (LysMCreIDTR) we selectively ablated LysM+ myelomonocytic cells 28d after MI for 10d via diphtheria toxin. We assessed a significantly improved vascular endothelial and smooth muscle function, less vascular superoxide production and a reduced expression of VCAM-1 and ATII receptor type 1 in aortic tissue. The number of circulating monocytes in blood was reduced, while the cardiac function (EF (%), LV size) in sonography stays constant between depleted and non-depleted HF mice. Conclusion: Our results suggest that vascular dysfunction post MI is at least in part mediated by inflammatory leukocyte infiltrating the vessel wall and that depletion of inflammatory monocytes in HF after MI improves the vascular function. It can potentially be a new target to protect endothelial function in HF and prevent secondary events after a MI.

scholarly journals Angiotensin II-induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen-activated protein kinase/arginase pathway

2011 ◽  
Vol 300 (5) ◽  
pp. C1181-C1192 ◽  
Author(s):  
Alia Shatanawi ◽  
Maritza J. Romero ◽  
Jennifer A. Iddings ◽  
Surabhi Chandra ◽  
Nagavedi S. Umapathy ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
P38 Mapk ◽  
Gene Knockout ◽  
Rho Kinase ◽  
Arginase Activity ◽  
No Production ◽  
Vascular Endothelial ◽  
Ang Ii ◽  
Vascular Endothelial Dysfunction

Enhanced vascular arginase activity impairs endothelium-dependent vasorelaxation by decreasing l-arginine availability to endothelial nitric oxide (NO) synthase, thereby reducing NO production. Elevated angiotensin II (ANG II) is a key component of endothelial dysfunction in many cardiovascular diseases and has been linked to elevated arginase activity. We determined signaling mechanisms by which ANG II increases endothelial arginase function. Results show that ANG II (0.1 μM, 24 h) elevates arginase activity and arginase I expression in bovine aortic endothelial cells (BAECs) and decreases NO production. These effects are prevented by the arginase inhibitor BEC (100 μM). Blockade of ANG II AT1 receptors or transfection with small interfering RNA (siRNA) for Gα12 and Gα13 also prevents ANG II-induced elevation of arginase activity, but siRNA for Gαq does not. ANG II also elevates active RhoA levels and induces phosphorylation of p38 MAPK. Inhibitors of RhoA activation (simvastatin, 0.1 μM) or Rho kinase (ROCK) (Y-27632, 10 μM; H1152, 0.5 μM) block both ANG II-induced elevation of arginase activity and phosphorylation of p38 MAPK. Furthermore, pretreatment of BAECs with p38 inhibitor SB-202190 (2 μM) or transfection with p38 MAPK siRNA prevents ANG II-induced increased arginase activity/expression and maintains NO production. Additionally, inhibitors of p38 MAPK (SB-203580, 5 μg·kg−1·day−1) or arginase (ABH, 8 mg·kg−1·day−1) or arginase gene knockout in mice prevents ANG II-induced vascular endothelial dysfunction and associated enhancement of arginase. These results indicate that ANG II increases endothelial arginase activity/expression through Gα12/13 G proteins coupled to AT1 receptors and subsequent activation of RhoA/ROCK/p38 MAPK pathways leading to endothelial dysfunction.

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