Cardiac-specific abrogation of NF- kappa B activation in mice by transdominant expression of a mutant I kappa B alpha
- PMID: 11133232
- DOI: 10.1006/jmcc.2000.1291
Cardiac-specific abrogation of NF- kappa B activation in mice by transdominant expression of a mutant I kappa B alpha
Abstract
Nuclear factor-kappaB (NF-kappa B) is a pleiotropic oxidant-sensitive transcription factor that is present in the cytosol in an inactive form complexed to an inhibitory kappaB (I kappa B) monomer. Various stimuli, including ischemia, hypoxia, free radicals, cytokines, and lipopolysaccharide (LPS), activate NF-kappa B by inducing phosphorylation of I kappa B. Phosphorylation of serine residues at positions 32 and 36 is critical for ubiquitination and degradation of I kappa B alpha with consequent migration of NF-kappa B to the nucleus. Although NF-kappa B is thought to contribute to numerous pathophysiologic processes, definitive assessment of its role has been hindered by the inability to achieve specific inhibition in vivo. Pharmacologic inhibitors of NF-kappa B are available, but their utility for in vivo studies is limited by their relative lack of specificity. Targeted ablation of genes encoding NF-kappa B subunits has not been productive in this regard because of fetal lethality in the case of p65 and functional redundancy in the Rel family of proteins. To overcome these limitations, we have created a viable transgenic mouse that expresses a phosphorylation-resistant mutant of I kappa B alpha (I kappa B alpha(S32A,S36A)) under the direction of a cardiac-specific promoter. Several transgenic lines were obtained with copy numbers ranging from one to seven. The mice exhibit normal cardiac morphology and histology. Total myocardial I kappa B alpha protein level is elevated 3.5- to 6.5-fold with a concomitant 50-60% decrease in the level of I kappa B beta. Importantly, expression of I kappa B(S32A,S36A) results in complete abrogation of myocardial NF-kappa B activation in response to tumor necrosis factor- alpha (TNF-alpha) and LPS stimulation. Thus, novel transgenic mice have been created that make it possible to achieve cardiac-specific and selective inhibition of NF-kappa B in vivo. These transgenic mice should be useful in studies of various cardiac pathophysiological phenomena that involve NF-kappa B activation, including ischemic preconditioning, heart failure, septic shock, acute coronary syndromes, cardiac allograft rejection, and apoptosis.
Similar articles
-
Regulation and function of IKK and IKK-related kinases.Sci STKE. 2006 Oct 17;2006(357):re13. doi: 10.1126/stke.3572006re13. Sci STKE. 2006. PMID: 17047224 Review.
-
Cardiac-specific blockade of NF-kappaB in cardiac pathophysiology: differences between acute and chronic stimuli in vivo.Am J Physiol Heart Circ Physiol. 2005 Jul;289(1):H466-76. doi: 10.1152/ajpheart.00170.2004. Epub 2005 Feb 4. Am J Physiol Heart Circ Physiol. 2005. PMID: 15695559
-
Differential regulation of myocardial NF kappa B following acute or chronic TNF-alpha exposure.J Mol Cell Cardiol. 2001 Jun;33(6):1263-71. doi: 10.1006/jmcc.2001.1388. J Mol Cell Cardiol. 2001. PMID: 11444928
-
Effect of NF-kappa B Inhibition on TNF-alpha-induced apoptosis and downstream pathways in cardiomyocytes.J Mol Cell Cardiol. 2001 Jun;33(6):1223-32. doi: 10.1006/jmcc.2001.1385. J Mol Cell Cardiol. 2001. PMID: 11444925
-
Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity.Annu Rev Immunol. 2000;18:621-63. doi: 10.1146/annurev.immunol.18.1.621. Annu Rev Immunol. 2000. PMID: 10837071 Review.
Cited by
-
Tyrosyl phosphorylation of PZR promotes hypertrophic cardiomyopathy in PTPN11-associated Noonan syndrome with multiple lentigines.JCI Insight. 2020 Aug 6;5(15):e137753. doi: 10.1172/jci.insight.137753. JCI Insight. 2020. PMID: 32584792 Free PMC article.
-
Ubiquitin-proteasome signaling in lung injury.Transl Res. 2018 Aug;198:29-39. doi: 10.1016/j.trsl.2018.04.003. Epub 2018 Apr 23. Transl Res. 2018. PMID: 29752900 Free PMC article. Review.
-
Proteomic characterization of epicardial-myocardial signaling reveals novel regulatory networks including a role for NF-κB in epicardial EMT.PLoS One. 2017 Mar 30;12(3):e0174563. doi: 10.1371/journal.pone.0174563. eCollection 2017. PLoS One. 2017. PMID: 28358917 Free PMC article.
-
Targeting TRAF3IP2 by Genetic and Interventional Approaches Inhibits Ischemia/Reperfusion-induced Myocardial Injury and Adverse Remodeling.J Biol Chem. 2017 Feb 10;292(6):2345-2358. doi: 10.1074/jbc.M116.764522. Epub 2017 Jan 4. J Biol Chem. 2017. PMID: 28053087 Free PMC article.
-
Mechanisms of transcription factor acetylation and consequences in hearts.Biochim Biophys Acta. 2016 Dec;1862(12):2221-2231. doi: 10.1016/j.bbadis.2016.08.011. Epub 2016 Aug 17. Biochim Biophys Acta. 2016. PMID: 27543804 Free PMC article. Review.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Molecular Biology Databases