Cardiomyocyte NF-κB p65 promotes adverse remodelling, apoptosis, and endoplasmic reticulum stress in heart failure.
OBJECTIVE
the role of nuclear factor (NF)-κB in heart failure (HF) is not well defined. We sought to determine whether myocyte-localized NF-κB p65 activation in HF exacerbates post-infarction remodelling and promotes maladaptive endoplasmic reticulum (ER) stress.


RESULTS
non-transgenic (NTg) and transgenic (Tg) mice with myocyte-restricted overexpression of a phosphorylation-resistant inhibitor of κBα (IκBα(S32A,S36A)) underwent coronary ligation (to induce HF) or sham operation. Over 4 weeks, the remote myocardium of ligated hearts exhibited robust NF-κB activation that was almost exclusively p65 beyond 24 h. Compared with sham at 4 weeks, NTg HF hearts were dilated and dysfunctional, and exhibited hypertrophy, fibrosis, up-regulation of inflammatory cytokines, increased apoptosis, down-regulation of ER protein chaperones, and up-regulation of the ER stress-activated pro-apoptotic factor CHOP. Compared with NTg HF, Tg-IκBα(S32A,S36A) HF mice exhibited: (i) improved survival, chamber remodelling, systolic function, and pulmonary congestion, (ii) markedly diminished NF-κB p65 activation, cytokine expression, and fibrosis, and (iii) a three-fold reduction in apoptosis. Moreover, Tg-IκBα(S32A,S36A) HF hearts exhibited maintained expression of ER chaperones and CHOP when compared with sham. In cardiomyocytes, NF-κB activation was required for ER stress-mediated apoptosis, whereas abrogation of myocyte NF-κB shifted the ER stress response to one of adaptation and survival.


CONCLUSIONS
persistent myocyte NF-κB p65 activation in HF exacerbates cardiac remodelling by imparting pro-inflammatory, pro-fibrotic, and pro-apoptotic effects. p65 modulation of cell death in HF may occur in part from NF-κB-mediated transformation of the ER stress response from one of adaptation to one of apoptosis.
Hamid
Tariq
T
Department of Medicine, Louisville VAMC and Institute of Molecular Cardiology, University of Louisville, ACB, 3rd Floor, 550 South Jackson Street, Louisville, Louisville, KY 40202, USA.
Guo
Shang Z
SZ
Kingery
Justin R
JR
Xiang
Xilin
X
Dawn
Buddhadeb
B
Prabhu
Sumanth D
SD
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D016207:Cytokines / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000502:physiology; D005355:Fibrosis; D006333:Heart Failure / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D013312:Stress, Physiological; D051996:Transcription Factor RelA / Q000502:physiology*; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology
D016207:Cytokines; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D050505:Mutant Proteins; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha
Circ Res. 2009 Jul 2;105(1):70-9
19478205
Circulation. 2010 May 4;121(17):1912-25
20404253
Mol Cell. 2002 Mar;9(3):625-36
11931769
Cold Spring Harb Symp Quant Biol. 1999;64:533-40
11232330
Circulation. 2004 Aug 10;110(6):705-12
15289376
Circ Res. 2002 Nov 29;91(11):988-98
12456484
J Mol Cell Cardiol. 2003 May;35(5):483-93
12738230
Circulation. 2003 Aug 12;108(6):638-40
12912791
Methods. 2001 Dec;25(4):402-8
11846609
Nat Rev Mol Cell Biol. 2004 May;5(5):392-401
15122352
Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3673-84
17921335
J Mol Med (Berl). 2004 Jul;82(7):434-48
15175863
Nat Cell Biol. 2001 Apr;3(4):409-16
11283615
Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6668-73
11381115
Am J Pathol. 2007 Aug;171(2):507-12
17556593
J Clin Invest. 2005 Oct;115(10):2625-32
16200195
Circulation. 1998 Jul 14;98(2):100-3
9679714
J Mol Cell Cardiol. 2001 Jan;33(1):161-73
11133232
Am J Cardiol. 2004 Sep 1;94(5):671-3
15342308
Circulation. 2009 Mar 17;119(10):1386-97
19255345
Circ Res. 2009 Mar 13;104(5):699-706
19168865
J Clin Invest. 2001 Feb;107(3):241-6
11160144
Circ Res. 2010 Jan 8;106(1):133-44
19850942
J Clin Invest. 2005 Oct;115(10):2656-64
16200199
FASEB J. 2006 Sep;20(11):1918-20
16837548
Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3537-42
9520401
Cardiovasc Res. 2002 Jan;53(1):124-30
11744020
Trends Cell Biol. 2009 Aug;19(8):404-13
19648011
Genes Dev. 2004 Sep 15;18(18):2195-224
15371334
Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1337-44
16632551
Circulation. 2000 May 2;101(17):2103-9
10790354
Endocrinology. 2009 Sep;150(9):4094-103
19556421
Clin Exp Immunol. 2004 Jan;135(1):64-73
14678266
EMBO Rep. 2006 Sep;7(9):880-5
16953201