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

Abstract

Myocardial Ca 2+ /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-κB pathway during both MI and exposure to bacterial endotoxin. CaMKII inhibition suppressed NF-κB 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.

A vital role for complement in heart disease

“…Conversely, C5a-receptor deficiency in a murine knock-out model has been associated with decreased resistance to cardiac stress, underscoring that complement might act as a double-edged sword also in the heart (Mullick et al, 2011). The mechanisms for in situ increased complement activation in heart failure are currently unknown, but myocardial levels of complement factor B are upregulated after myocardial infarction through toll-like receptor signaling and inflammatory cytokines (Singh et al, 2009;Singh et al, 2012). Complement factor B deficient mice subjected to myocardial infarction have improved survival and cardiac function, less cardiac hypertrophy, and importantly, markedly reduced myocardial C3 deposition.…”

Mammalian DNA Is an Endogenous Danger Signal That Stimulates Local Synthesis and Release of Complement Factor B

“…It has been previously demonstrated that factor B is upregulated 3 wks after myocardial infarction in a murine model (22). We have observed that factor B is upregulated in hearts that underwent cold I/R compared with control hearts in a syngeneic, heterotopic cardiac transplant model (Supplementary Figure S1).…”

“…More recently, it has been shown that local production of factor B is markedly upregulated in a murine myocardial infarction model. In the same study, factor B -/-mice demonstrated less myocardial complement deposition and less adverse remodeling after ischemic myocardial injury (22). In aggregate, these observations highlight the importance of factor B in local tissue damage caused by autoimmunity and demonstrate that local production of factor B is important to the pathogenesis of ischemic tissue injury as well.…”

“…Factor B plays an important role in ischemic tissue injury (20,22,32). It has been previously demonstrated that factor B is upregulated 3 wks after myocardial infarction in a murine model (22).…”

CARMA3: A novel scaffold protein in regulation of NF-κB activation and diseases

“…NF-κB was first identified as a transcription factor of immunoglobulin κ light chain in B cells and is characterized by its important roles in the immune system [4] . NF-κB is now known to be ubiquitously expressed in all cell types and has prominent roles in tumorigenesis and the development of neural, heart and immune diseases [4][5][6][7][8] .…”