Blockade of NF-κB improves cardiac function and survival after myocardial infarction

Abstract

NF-kappaB is a key transcription factor that regulates inflammatory processes. In the present study, we tested the hypothesis that blockade of NF-kappaB ameliorates cardiac remodeling and failure after myocardial infarction (MI). Knockout mice with targeted disruption of the p50 subunit of NF-kappaB (KO) were used to block the activation of NF-kappaB. MI was induced by ligation of the left coronary artery in male KO and age-matched wild-type (WT) mice. NF-kappaB was activated in noninfarct as well as infarct myocardium in WT+MI mice, while the activity was completely abolished in KO mice. Blockade of NF-kappaB significantly reduced early ventricular rupture after MI and improved survival by ameliorating congestive heart failure. Echocardiographic and pressure measurements revealed that left ventricular fractional shortening and maximum rate of rise of left ventricular pressure were significantly increased and end-diastolic pressure was significantly decreased in KO+MI mice compared with WT+MI mice. Histological analysis demonstrated significant suppression of myocyte hypertrophy as well as interstitial fibrosis in the noninfarct myocardium of KO+MI mice. Blockade of NF-kappaB did not ameliorate expression of proinflammatory cytokines in infarct or noninfarct myocardium. In contrast, phosphorylation of c-Jun NH2-terminal kinase was almost completely abolished in KO+MI mice. The present study demonstrates that targeted disruption of the p50 subunit of NF-kappaB reduces ventricular rupture as well as improves cardiac function and survival after MI. Blockade of NF-kappaB might be a new therapeutic strategy to attenuate cardiac remodeling and failure after MI.

Myocardial fibrosis in response to Angiotensin II is preceded by the recruitment of mesenchymal progenitor cells

“…This theory has been supported by the identification of mononuclear cells, positive for macrophage markers, in the infiltrating cell population. 7,8,[11][12][13] Cell phenotypes, and marker expression, are dynamic and cells can alter their molecular expression to respond appropriately to stimuli in their environmental milieu. There is a circulating monocyte/macrophage precursor population that expresses specific markers for this cell type but are a phenotypically heterogeneous population.…”

“…This has led some investigators to suggest that these cells are of the monocyte/ macrophage lineage. 7,8,[11][12][13] One should note that cells that stain positive for monocyte/macrophage markers do not account for all the infiltrating cells. 7,8,11 This observation suggests a role for a yet to be described cell type.…”

Multiple Facets of NF-κB in the Heart

“…71,72 Furthermore, p50 Ϫ/Ϫ mice display reduced cardiac hypertrophy following myocardial infarction or during TNF␣-induced cardiomyopathy. 73,74 However, NF-B inhibition could not overcome hypertrophy in in vivo studies using higher gradient aortic banding, nor did NF-B inhibition alter the course of stress-induced remodeling, which has raised the question of whether NF-B is associated with adaptive or maladaptive hypertrophy. 72 In addition, it remains to be demonstrated how NF-B induces cardiac hypertrophy and fetal gene expression, because, to our knowledge, NF-B binding sites have not been identified in the promoter regions of adult or fetal cardiac genes associated with cardiac growth.…”

Inhibition of NF-κB improves left ventricular remodeling and cardiac dysfunction after myocardial infarction

“…Despite several studies that have mentioned the potential role of NF-B in the pathogenesis of cardiac remodeling, only a few studies have examined the effect of continuous inhibition of NF-B on myocardial remodeling after MI (15,30), and its mechanism has not been fully elucidated yet. Therefore, we sought to determine whether blocking of NF-B by phosphorylation inhibitor of I B, IMD-0354 (IMD), ameliorates progressive LV remodeling after experimental MI.…”