Cardiomyocyte-specific p65 NF-κB deletion protects the injured heart by preservation of calcium handling

Abstract

NF-κB is a well-known transcription factor that is intimately involved with inflammation and immunity. We have previously shown that NF-κB promotes inflammatory events and mediates adverse cardiac remodeling following ischemia reperfusion (I/R). Conversely, others have pointed to the beneficial influence of NF-κB in I/R injury related to its anti-apoptotic effects. Understanding the seemingly disparate influence of manipulating NF-κB is hindered, in part, by current approaches that only indirectly interfere with the function of its most transcriptionally active unit, p65 NF-κB. Mice were generated with cardiomyocyte-specific deletion of p65 NF-κB. Phenotypically, these mice and their hearts appeared normal. Basal and stimulated p65 expression were significantly reduced in whole hearts and completely ablated in isolated cardiomyocytes. When compared with wild-type mice, transgenic animals were protected from both global I/R by Langendorff as well as regional I/R by coronary ligation and release. The protected, transgenic hearts had less cytokine activity and decreased apoptosis. Furthermore, p65 ablation was associated with enhanced calcium reuptake by the sarcoplasmic reticulum. This influence on calcium handling was related to increased expression of phosphorylated phospholamban in conditional p65 null mice. In conclusion, cardiomyocyte-specific deletion of the most active, canonical NF-κB subunit affords cardioprotection to both global and regional I/R injury. The beneficial effects of NF-κB inhibition are related, in part, to modulation of intracellular calcium homeostasis.

MCP-1-induced protein attenuates post-infarct cardiac remodeling and dysfunction through mitigating NF-κB activation and suppressing inflammation-associated microRNA expression

“…Although MCPIP was reported to promote inflammatory angiogenesis [39,44,47], no significant difference in the immunohistochemically detectable capillary density in the post-MI hearts was observed between the two groups, probably due to targeted MCPIP expression in cardiomyocytes, but not in the endothelial cells or monocytic cells that are known to be involved in postischemic neovascularization [2]. Failing hearts exhibit chronic activation of NF-jB and sustained inflammation [16,29], and blockage of NF-jB has been shown to protect heart from advanced remodeling after MI [17,25,58]. MCPIP was reported to inhibit NFjB activation in other cell types [26,49].…”

“…Cardiomyocytes comprises about 20-30 % of all cells within the heart, and they also express TLRs and can be a significant source of innate immune responses [12,15,17,29]. Extensive experimental evidence by gain-and loss-offunction studies suggests that persistent NF-jB activation in cardiomyocytes can cause cardiomyopathy and heart failure by mounting a robust inflammatory response that is common in the context of ischemic injury [17,29,58]. Various approaches that minimize inflammation to the heart have been shown to improve left ventricular remodeling and dysfunction following MI.…”

Resolvin D1 Reduces Infarct Size Through a Phosphoinositide 3-Kinase/Protein Kinase B Mechanism

“…This finding is in agreement with a model of lung injury in which RvD1 reduces inflammation and NF-ĸB through a mechanism involving peroxisome proliferator-activated receptor gamma. 32 Several authors have reported that NF-ĸB inhibition confers cardioprotection, [33][34][35] whereas others suggest that its activation is necessary for cardioprotection. 36 Although we observed NF-ĸB inhibition and reduction of leukocyte accumulation in ischemic regions, we believe that these effects are not sufficient to induce cardioprotection, because similar results were obtained in the 0.01-mg group in which RvD1 had no significant influence on infarct size.…”

The Biological Basis for Cardiac Repair After Myocardial Infarction

“…79 Acute NF-κB activation is essential for late cardioprotection induced by ischemic preconditioning. 96, 97 However, mice with cardiomyocyte-restricted overexpression of phosphorylation-resistant IκBα, 98 cardiomyocyte-specific p65 deletion, 99 IκBα overexpression via gene transfer, 100 NF-κB double-stranded decoy DNA transfection, 101 and pharmacological blockade of IκBα 102 or IKKβ 103 have demonstrated that NF-κB inhibition (primarily in cardiomyocytes and perhaps more related to p65) during myocardial I/R decreases infarct size, reduces inflammatory responses including leukocyte infiltration, and improves cardiac function. Studies of non-reperfused MI in mice with cardiomyocyte-restricted overexpression of phosphorylation-resistant IκBα 95 or A20 (NF-κB signaling inhibitor), 104 and IκBα gene transfer 105 have similarly shown that blocking NF-κB (mainly p65 based on time course studies 95 ) attenuates long-term adverse cardiac remodeling, dysfunction, and inflammation.…”