Xiaoyu Kan1, Yina Wu1, Youcai Ma1, Congcong Zhang1, Ping Li2, Lifei Wu1, Shuai Zhang1, Yulin Li3, Jie Du3. 1. Beijing Anzhen Hospital, Capital Medical University, Beijing, China Beijing Institute of Heart Lung and Blood Vessel Diseases, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovative Research Center for Cardiovascular Diseases, Beijing 100029, China. 2. Beijing Anzhen Hospital, Capital Medical University, Beijing, China. 3. Beijing Anzhen Hospital, Capital Medical University, Beijing, China Beijing Institute of Heart Lung and Blood Vessel Diseases, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovative Research Center for Cardiovascular Diseases, Beijing 100029, China jdu@bcm.edu lyllyl_1111@163.com.
Abstract
AIMS: IL-12p35 is a pro-inflammatory cytokine that participates in a variety of inflammatory diseases. This study aimed to determine whether IL-12 regulates cardiac injury and repair following acute myocardial infarction (AMI) and investigate the underlying mechanisms. METHODS AND RESULTS: Mice with AMI showed a marked increase in IL-12p35 expression of ischaemic cardiac tissues. IL-12 was mainly produced by CD11b(+) monocytes. Cardiac functions were significantly improved in IL-12p35 knockout (p35-KO) mice compared with wild-type (WT) littermates in response to AMI. IL-12p35 deficiency attenuated the infarct scar and hypertrophy compared with WT mice. RNA transcriptome sequencing and quantitative RT-PCR analysis of CD11b(+) monocytes isolated from WT and p35-KO ischaemic hearts revealed a distinct transcriptional profile in p35-KO CD11b(+) monocytes, displaying pro-angiogenesis and anti-inflammation properties. Angiogenesis was enhanced in p35-KO mice with AMI and hindlimb ischaemia. Moreover, tube formation assay and Matrigel plug analysis demonstrated that IL-12 inhibition of angiogenesis was dependent on monocytes. IL-12p35 deficiency inhibited inflammation by reducing chemokine production and monocyte infiltration into the heart. Finally, administration of an IL-12p35-neutralizing antibody limited AMI-induced inflammatory cell infiltration into the heart and improved angiogenesis and cardiac function. CONCLUSIONS: Deficiency of IL-12p35 limited AMI-induced cardiac injury by promoting pro-angiogenesis and anti-inflammatory functions of monocytes. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: IL-12p35 is a pro-inflammatory cytokine that participates in a variety of inflammatory diseases. This study aimed to determine whether IL-12 regulates cardiac injury and repair following acute myocardial infarction (AMI) and investigate the underlying mechanisms. METHODS AND RESULTS:Mice with AMI showed a marked increase in IL-12p35 expression of ischaemic cardiac tissues. IL-12 was mainly produced by CD11b(+) monocytes. Cardiac functions were significantly improved in IL-12p35 knockout (p35-KO) mice compared with wild-type (WT) littermates in response to AMI. IL-12p35deficiency attenuated the infarct scar and hypertrophy compared with WT mice. RNA transcriptome sequencing and quantitative RT-PCR analysis of CD11b(+) monocytes isolated from WT and p35-KO ischaemic hearts revealed a distinct transcriptional profile in p35-KO CD11b(+) monocytes, displaying pro-angiogenesis and anti-inflammation properties. Angiogenesis was enhanced in p35-KO mice with AMI and hindlimb ischaemia. Moreover, tube formation assay and Matrigel plug analysis demonstrated that IL-12 inhibition of angiogenesis was dependent on monocytes. IL-12p35 deficiency inhibited inflammation by reducing chemokine production and monocyte infiltration into the heart. Finally, administration of an IL-12p35-neutralizing antibody limited AMI-induced inflammatory cell infiltration into the heart and improved angiogenesis and cardiac function. CONCLUSIONS: Deficiency of IL-12p35 limited AMI-induced cardiac injury by promoting pro-angiogenesis and anti-inflammatory functions of monocytes. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Maha Ali; Vishal Mali; Samuel Haddox; Soad M AbdelGhany; Sahar E M El-Deek; Atif Abulfadl; Khalid Matrougui; Souad Belmadani Journal: Am J Pathol Date: 2017-08-22 Impact factor: 4.307