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Ca2+/calmodulin-dependent kinase II triggers cell membrane injury by inducing complement factor B gene expression in the mouse heart
Journal article   Open access   Peer reviewed

Ca2+/calmodulin-dependent kinase II triggers cell membrane injury by inducing complement factor B gene expression in the mouse heart

Madhu V Singh, Ann Kapoun, Linda Higgins, William Kutschke, Joshua M Thurman, Rong Zhang, Minati Singh, Jinying Yang, Xiaoqun Guan, John S Lowe, …
The Journal of clinical investigation, Vol.119(4), pp.986-996
04/2009
DOI: 10.1172/JCI35814
PMCID: PMC2662543
PMID: 19273909
url
https://doi.org/10.1172/JCI35814View
Published (Version of record) Open Access

Abstract

Myocardial Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibition improves cardiac function following myocardial infarction (MI), but the CaMKII-dependent pathways that participate in myocardial stress responses are incompletely understood. To address this issue, we sought to determine the transcriptional consequences of myocardial CaMKII inhibition after MI. We performed gene expression profiling in mouse hearts with cardiomyocyte-delimited transgenic expression of either a CaMKII inhibitory peptide (AC3-I) or a scrambled control peptide (AC3-C) following MI. Of the 8,600 mRNAs examined, 156 were substantially modulated by MI, and nearly half of these showed markedly altered responses to MI with CaMKII inhibition. CaMKII inhibition substantially reduced the MI-triggered upregulation of a constellation of proinflammatory genes. We studied 1 of these proinflammatory genes, complement factor B (Cfb), in detail, because complement proteins secreted by cells other than cardiomyocytes can induce sarcolemmal injury during MI. CFB protein expression in cardiomyocytes was triggered by CaMKII activation of the NF-kappaB pathway during both MI and exposure to bacterial endotoxin. CaMKII inhibition suppressed NF-kappaB activity in vitro and in vivo and reduced Cfb expression and sarcolemmal injury. The Cfb-/- mice were partially protected from the adverse consequences of MI. Our findings demonstrate what we believe is a novel target for CaMKII in myocardial injury and suggest that CaMKII is broadly important for the genetic effects of MI in cardiomyocytes.
 Myocardial Infarction - genetics Oligonucleotide Array Sequence Analysis Peptides - genetics NF-kappa B - metabolism Gene Expression Profiling RNA, Messenger - metabolism Peptides - metabolism Complement Factor B - genetics Myocardial Infarction - pathology Myocardium - metabolism Cell Membrane - metabolism Complement Factor B - deficiency Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism Gene Expression Lipopolysaccharides - toxicity RNA, Messenger - genetics Mice, Transgenic Myocardial Infarction - metabolism Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors Mice, Knockout Myocytes, Cardiac - pathology Animals Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Mice

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