IKKβ inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury

Abstract

Moss NC, Stansfield WE, Willis MS, Tang R, Selzman CH. IKK␤ inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 293: H2248-H2253, 2007. First published August 3, 2007;. doi:10.1152/ajpheart.00776.2007.-Despite years of experimental and clinical research, myocardial ischemia-reperfusion (IR) remains an important cause of cardiac morbidity and mortality. The transcription factor nuclear factor-B (NF-B) has been implicated as a key mediator of reperfusion injury. Activation of NF-B is dependent upon the phosphorylation of its inhibitor, IB␣, by the specific inhibitory B kinase (IKK) subunit, IKK␤. We hypothesized that specific antagonism of the NF-B inflammatory pathway through IKK␤ inhibition reduces acute myocardial damage following IR injury. C57BL/6 mice underwent left anterior descending (LAD) artery ligation and release in an experimental model of acute IR. Bay 65-1942, an ATP-competitive inhibitor that selectively targets IKK␤ kinase activity, was administered intraperitoneally either prior to ischemia, at reperfusion, or 2 h after reperfusion. Compared with untreated animals, mice treated with IKK␤ inhibition had significant reduction in left ventricular infarct size. Cardiac function was also preserved following pretreatment with IKK␤ inhibition. These findings were further associated with decreased expression of phosphorylated IB␣ and phosphorylated p65 in myocardial tissue. In addition, IKK␤ inhibition decreased serum levels of TNF-␣ and IL-6, two prototypical downstream effectors of NF-B activity. These results demonstrate that specific IKK␤ inhibition can provide both acute and delayed cardioprotection and offers a clinically accessible target for preventing cardiac injury following IR.inhibitory B kinase-␤; myocardial infarction; nuclear factor-B CORONARY HEART DISEASE IS RESPONSIBLE for nearly one of every five deaths in the U.S. Survivors of acute coronary syndromes are 15 times more prone to develop additional cardiovascular morbidity and mortality (28). These outcomes persist despite three decades of experimental and clinical research. Successful treatment strategies for acute myocardial infarction, including systemic thrombolytics or percutaneous coronary artery angioplasty, are specifically directed toward the ischemic source of myocardial damage. The associated reperfusion injury, however, has remained an elusive therapeutic target. Thousands of animal studies have been performed investigating pharmacological and procedural methods to limit myocardial injury after ischemic events, yet few have been reproducible or shown clinical promise (4). As such, a continued need exists to develop cardioprotective therapies for reperfusion injury that can be translated successfully into clinical practice.Reperfusion injury is associated with an inflammatory cascade that perpetuates further damage to cardiac tissue after a period of ischemia. One of the central players upregulated during this process is the transcription factor...

The immune system and cardiac repair

“…In vivo transfer of NF-κB decoy oligodeoxynucleotides to bind the transcriptional factor blocking inflammatory gene activation, reduced the extent of myocardial infarction following reperfusion suggesting a crucial role for NF-κB in the regulation of the post-infarction inflammatory response [78]. In addition, treatment with an IKKβ inhibitor attenuated IκBα phosphorylation reduced infarct size, improved cardiac function and decreased proinflammatory cytokine levels in a model of reperfused infarction [79]. Furthermore, transgenic mice with cardiac-specific expression of a dominant-negative IκBα resulting in inhibition of cardiomyocyte NF-κB activation, exhibited significantly decreased infarct size in a model of reperfused infarction [80], and NF-κB p50 null mice had improved early survival and reduced left ventricular dilatation after non-reperfused infarction [81].…”

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

“…In addition, blocking MyD88, the downstream adapter of TLR-4 signaling, displays similar protection against myocardial injury (51). Moreover, several studies have underlined the role of the NF-κB pathway in cardiac hypertrophy and inflammation (52)(53)(54)(55). Since the NF-κB pathway is one of the major proinflammatory pathways to be induced by TLR activation, it is likely that a subgroup of inflammatory genes, including Cfb, is induced by TLR-4 activation upon myocardial injury.…”

Feed-forward signaling of TNF-α and NF-κB via IKK-β pathway contributes to insulin resistance and coronary arteriolar dysfunction in type 2 diabetic mice

“…Recent studies noted that NF-B blockade by inhibiting IKK-␤ activity decreased myocardial injury and preserved cardiac function following ischemia-reperfusion (26), which supports the concept that the inflammatory response participates in the development of heart failure (42). Our results show that p-IKK-␤ increases in diabetes, but the blockade of NF-B and oxidative stress and the genetic deletion of TNF-␣ attenuated p-IKK-␤, suggesting that the phosphorylation of IKK-␤ increases in diabetic mice by the activation of oxidative stress and TNF-␣.…”

“…IKK-␤, the molecular target of NaSal, is associated with the rise of insulin resistance (7,43). Recent work suggests that a specific antagonism of the NF-B inflammatory pathway through the inhibition of IKK-␤ reduces acute myocardial damage following ischemia-reperfusion injury (26) and that insulin action plays a critical role in reducing myocardial infarct size by increasing cardiac myocyte metabolism (5,8,29). We previously found that TNF-␣-activated Jun NH 2 -terminal kinase (JNK), which mediates O 2 Ϫ production and impairs endothelium-dependent, nitric oxide (NO)-mediated vasodilation in coronary arterioles (45).…”