Table 3.

Mouse models of the NF-κB signaling pathway resembling ageing-associated heart diseases.

NF-κB Gene	Genetic Modification	Age-Related Disease
		Heart Diseases
Nfkb1 [130]	Nfkb1-KO mice. Chronic infusion of angiotensin II, increases systemic blood pressure and pro-inflammatory cytokines in the myocardium and provokes ventricular hypertrophy.	Cardiac hypertrophy Nfkb1-deficiency attenuates myocardial inflammation and hypertrophy in response to chronic infusion of angiotensin II without deteriorating cardiac function. Blockade NF-κB activation leads to abrogation of JNK phosphorylation in response to chronic infusion of angiotensin II. Mice from 8- to 12-week-old were analyzed.
Nfkb1 [133]	Nfkb1-KO mice. Cross of Nfkb1-KO mice with TNF-TG mice (with cardiac-specific overexpression of TNF-α) as a model of cytokine-induced cardiomyopathy.	Cardiac dysfunction and remodeling Blockade of NF-κB in Nfkb1-KO mice reverses cardiac dysfunction and remodeling; improves cardiac function and survival without affecting inflammation in TNF-α-induced cardiomyopathy; it also blocks MMP-9 activation. Neonatal to 12-week-old mice were studied.
Nfkb1 [132]	Nfkb1-deficient mice. Myocardial infarction was induced by ligation of the left coronary artery.	Myocardial infarction Targeted disruption of Nfkb1 reduces ventricular rupture, and improves cardiac function and survival after myocardial infarction (MI) with amelioration of myocyte hypertrophy and interstitial fibrosis. Mechanisms proposed are: chronic inhibition of NF-κB; amelioration of myocyte hypertrophy and interstitial fibrosis; selective abrogation of JNK phosphorylation; lower infarction area. Mice from 8- to 26-week-old were analyzed.
Nfkb1 [131]	Nfkb1-deficient mice. Myocardial infarction was induced by ligation of the left coronary artery.	Myocardial infarction Absence of the NF-κBp50 subunit improves early survival and reduces left ventricular dilatation after myocardial infarction. Absence of the NF-κBp50 subunit reduces collagen content and MMP-9 expression after myocardial infarction (which are involved in progressive left ventricular remodeling). Mice from 8- to 24 weeks of age were analyzed.
Ikkβ, Iκbα, Nemo [134]	Tet O.IKKβ-CA mice. Inducible transgenic mice with cardiomyocyte-specific expression of constitutively active IKKβ. IκBα-3M; IKKβ-DN, mice with a floxed Nemo allele. For induction of viral myocarditis, mice were infected intraperitoneally with purified CVB3.	Cardiomyopathy and heart failure In adult animals, IKKβ activation led to inflammatory dilated cardiomyopathy and heart failure. Upon transgene inactivation, the disease was reversed, even at an advanced stage. In vivo expression of the IκBα superrepressor prevented the development of the disease. Constitutively active IKKβ expression induces myocyte atrophy; excessive inflammatory response with enhanced levels of inflammatory cytokines, and an IFN type I signature, with activation of the IFN-stimulated gene 15 (ISG15) pathway. In cardiomyocytes lacking Nemo, the induction of ISG15 was attenuated. Mice from 4- to 24-week-old were studied.
Ikbα [135]	Tg-IκBαS32A,S36A mice with myocyte-specific expression of a transdominant mutant human IκBα (α-MyHC promoter) HF induced by surgery.	Heart failure Tg-IκBαS32A,S36A mice exhibit improved post-infarction survival and alleviated LV remodeling, They do not show pro-inflammatory cytokine expression or fibrosis. Display decreased apoptosis and stimulated adaptive endoplasmic reticulum stress responses in HF systolic function. Myocyte NF-κB abrogation induces a marked decrease of both NF-κB p65 activation and cytokine expression. Mice from 10- to 24-week-old were analyzed.
Rela [136]	Cardiac-specific deletion of Rela using a Cre-loxP system.	Cardiac hypertrophy and remodeling Rela deficiency in the heart of mouse decreases the hypertrophic response after pressure overload stimulation, and the degree of pathological remodeling, while preserves contractile function. Transcriptional regulatory mechanism whereby NF-κB and NFAT directly interact and synergistically promote transcriptional activation in cardiomyocytes. 8- and 12-week-old mice were studied.
		Atherosclerosis
Nfkb1 [139]	Nfkb1−/− mice, subjected to chronic intermittent hypoxia (CIH) and high cholesterol diet (HCD).	Nfkb1 gene deletion diminished CIH + HCD-induced NF-κB activation and abolished CIH + HCD induced atherosclerosis. Nfkb1 gene deletion through the blockage of NF-κB activation inhibits CIH + HCD-induced activation of three major atherogenic mechanisms: vascular wall inflammation, hypercholesterolemia (p50 reduces serum cholesterol level), and macrophage foam cell formation. Mice between 7- and 42.6-week-old were analyzed.
Nfkb1 [140]	Apoe-KO mice and mice deficient in Nfkb1 gene (p50-KO) were crossed and obtained ApoE-p50-DKO mice.	CIH downregulates hepatic low-density lipoprotein receptor and HMG-CoA reductase expression in ApoE-p50-DKO but not in ApoE-KO mice, showing the protective role of p50 in CIH-induced atherosclerosis by inhibiting CIH-induced inflammation and hypercholesterolemia. 7- to 37-week-old were analyzed.
Ikkγ, IkBα [138]	Endothelium-restricted inhibition of NF-κB by ablation of Nemo/IKKγ or expression of dominant-negative IkBα in ApoE-KO mice: Tie1NEMOEC-KO/ApoE−/−;Tie2NEMOEC-KO/ApoE−/− (this latter tamoxifen-induced); and Tie2DNIkBa/ApoE−/− mice were used.	IKKγ or IkBα ablation in endothelial cells of ApoE−/− mice (a well-established mouse model of atherosclerosis), reduced atherosclerotic plaque formation in mice fed with a cholesterol rich diet. Inhibition of NF-κB activation abrogates adhesion molecule induction in endothelial cells, impaired macrophage recruitment to atherosclerotic plaques, and reduced expression of cytokines and chemokines in the aorta. Mice between 8- and 18-week-old were analyzed
Ikkβ [144]	Ikkβ deficiency in smooth muscle cells (SMCs) driven by a SM22Cre-Ikkβ-flox system. To increase susceptibility to spontaneous atherosclerotic lesion development, the SM22Cre+IkkβF/F mice were crossed with LDLR−/− mice.	Deficiency of IKKβ in SMCs rendered low density lipoprotein receptor-null mice resistant to vascular inflammation and atherosclerosis induced by high-fat feeding. SM22Cre+IkkBF/FLDLR−/− mice had decreased levels of inflammatory cytokines (IL-1β, TNF-α, and MCP-1) in the atherosclerotic lesions, arterial walls, and plasma, indicating a reduction in vascular inflammation associated with chronic inflammation. 16-week-old mice were analyzed.