The activation of NF-κB is critical in the pathological processes of most CVDs. NF-κB mediates inflammation, cell survival, cell differentiation and cell proliferation which contribute to the pathogenesis of CVDs such as hypertension, atherosclerosis and related manifestations such as myocardial ischemia and infarction, cerebrovascular ischemia and strokes, heart failure and cardiac hypertrophy. NF-κB activation also regulates extracellular matrix formation by affecting the production of matrix metalloproteinases (MMPs) and collagens in a variety of cells in the cardiovascular system (Fig. 3). Upon induction of NF-κB, inflammatory cytokines, chemokines as well as adhesion molecules are generated from innate and adaptive immune cells, such as macrophages, neutrophils, dendritic cells, T cell and B cells. The subsequent inflammatory process leads to injury in tissues and organs of cardiovascular system (Fig. 3).
Atherosclerosis is a chronic inflammatory disorder characterized by the accumulation of lipids particles in arterial walls with pathological risk to heart attack or stroke [40–42]. The activated NF-κB signaling is involved in all stages of atherosclerosis development .
The initiation of atherosclerosis is mediated by (endothelial cell) EC activation and engulfment of oxidized low-density lipoproteins (ox-LDLs). Upon stimulation by various stimuli, vascular ECs express cytokines, chemokines and cell adhesion molecules which facilitate the recruitment of circulated leukocytes and their migration to the subendothelial layer of arterial intima. The essential role of NF-κB-mediated signaling cascade has been shown in this process [43–47]. Various pro-atherogenic molecules, including cytokines like TNF-α, IL-1, bacterial and viral infections, ox-LDL, ROS and advanced glycation endproducts (AGEs), activate NF-kB [48–52]. NF-κB mediated downstream canonical and non- canonical signaling pathways are involved in different aspects of atherosclerotic process . Subsequent induction of a large array of molecules in the ECs, such as ICAM-1, VCAM-1, P- and E-selectins, TNF-α, IL-1, IL-6, IL-8, MCP-1 and MMPs, promote the recruitment of innate and adaptive immune cells to the vessel wall [44, 53, 54]. It is noteworthy that conditional deletion of NEMO or transgenic expression of dominant-negative IκBα leads to inhibition of expression of adhesion molecules in vascular ECs and impaired monocyte/macrophage recruitment to atherosclerotic plaques in ApoE KO mice fed high-fat diet. Subsequently, there is a reduction in the severity of atherosclerosis .
Further, Ox-LDL mediated TLR activation in vascular ECs results in the upregulation of NF-κB induced expression of proinflammatory cytokines and adhesion molecules, triggering atherosclerotic progress of inner coat of the blood vessels [45, 55–57]. Importantly, the degree of atherosclerosis was shown to be inhibited by suppressing TLR2/4-MyD88 signaling with decreased expression of chemokine and macrophage recruitment [45, 55].
Fluid mechanical force is another factor that regulates NF-κB expression and activity in ECs. Enhanced NF-κB (p50 and p65) activation was showed in human aortic ECs under steady low shear stress than under high shear stress  (Fig. 4). The increased NF-κB activity in blood flow stressed ECs and susceptibility to atherosclerosis suggest that disturbed blood flow induced NF-κB activation in vascular ECs might be involved in the early stages of atherogenesis by facilitating monocyte/macrophage recruitment and plaque formation [45, 59, 60]. In early state of atherogenesis when NF-κB is activated, ROS acts as second messenger in response to extracellular stimuli such as ox-LDL and Ang II (angiotensin II). Ox-LDL mediated ROS generation results in reduced NO production with subsequent further increase in NF-κB activation . Ang II is the most important mediator of the RAAS (renin–angiotensin–aldosterone system) in state of high blood pressure. Ang II-ROS-NF-κB activation links hypertension to increased risk factor of atherosclerosis [62–65].
NF-κB is also involved in differentiation of monocytes into macrophages after their recruitment to the intima . The macrophages express surface scavenger receptors, such as lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), SR-A and CD36 which facilitate binding and uptake the native and oxidized form of LDL as a protective reaction to eliminate the accumulation of these inflammatory components . As a consequence, the damage caused by modified LDLs to vascular ECs and smooth muscle cells is reduced. CD36-mLDL interaction induces LDL absorption, oxidative stress, and the production of proinflammatory cytokines through NF-kB activation [67, 68]. The various forms of LDL phagocytosis results in overconsumption of cholesterol in the cytoplasm and this cellular event converts the macrophages into foam cells. foam cell formation and aggregation on the arterial vessels promotes the development of fatty streaks [40, 69]. Enrichment of lipids, foam cells and T-lymphocytes has been identified in early lesions. The NF-κB activation has also been characterized in smooth muscle cells, macrophages and T-cells in progressing atherosclerotic lesions . NF-κB mediated M-CSF generation is involved in monocyte-to-macrophage differentiation . NF-κB mediated MMP-9 expression contributes to the degradation of extracellular matrix, facilitating the migration of monocyte/macrophages into the target tissues . Reduced macrophage infiltration and reduced vessel media damage and limited progression of atherosclerosis have been shown in MMP-9 and apoE dual deficiency mice . Short periods of stimulation of monocytes with ox-LDL activates NF-κB and its target genes while longer-time stimulation reverse these responses . Ox-LDL-NF-κB mediated chemokines production strengthen inflammatory effect by promoting the resident macrophages proliferation and migration of new monocytes into lesion sites . In addition, ox-LDL-NF-κB mediated pro-inflammatory cytokines expression promotes the binding of LDL to ECs and smooth muscle cells (SMCs) and upregulates the expression of CD36, leading to further inflammation .
Atherosclerotic lesion development involves migration of SMCs from the vessel wall media into the intima from where proliferation of the SMCs and ECM formation occur. This event drives the early atherosclerotic lesion and fibrotic cap formation. NF-κB activation plays a critical role in this pathological process. Activated NF-kB p65 and p50 components have been identified in SMCs derived from human atherosclerotic lesions compared to SMCs from healthy tissues . Also, several activated NF-κB components including p65, p50 and c-Rel have been found in cells isolated from human atherosclerotic tissue . Vascular SMCs convert from health contractile phenotype to pathological fibroblast-like synthetic phenotype which is the major source of connective tissue in the lesion site. This switching progress is an important step in atherosclerotic pathology [75, 76]. In vitro studies have shown that the production of TNF-α, IL-1, M-CSF, GMCSF, or MCP-1 is regulated by NF-κB in synthetic-state SMCs [70, 77–80]. These inflammatory molecules produced by SMCs, monocyte/macrophages, ECs, as well as lymphocytes induce the activation of NF-κB in an autocrine manner [70, 78]. NF-κB signaling in ECs may promote recruitment and activation of inflammatory cells, whereas NF-κB activity in SMCs leads to their proliferation .
In later stages of atherosclerosis, programmed lipid-laden cells death (apoptosis) is an important feature; it controls the stability of the lesion and the generation of the necrotic core. Apoptosis plays an essential role in atherogenesis and its progression in all stages of atherosclerosis . Clearance of dead cells derived from foam cells apoptosis by the innate and adaptive immune system in early lesions suppresses macrophage burden and inhibits atherosclerosis progression. However, in the late stages of atherosclerosis, impaired ability to clear dead foam cells facilitates the growth of lipid core, leading to inflammation, necrosis, and reduced stability of plaque. These pathological events increase the risk of rupture of an unstable atherosclerotic lesion, which causes acute vascular diseases such as stroke and acute myocardial infarction/ ischemia [83–86].
In atherosclerosis, NF-κB pathway exhibits its dual effect in cell survival/apoptosis in the context of various activating stimuli [87, 88]. NF-κB promotes survival signal by inhibiting TNFRs mediated apoptosis signal while it contributes to apoptosis through regulation of ROS generation and activation of the JNK- MAPK signal transduction [87, 89–91]. Activation of NF-κB increases the expression of Fas ligand which induces cell apoptosis via its receptor CD95. IκB kinase (IKK) promotes NF-κB-induced anti-apoptotic signal by mediating phosphorylation and degradation of the NF-κB inhibitory IκBα proteins [41, 87], and inhibition of IKK-mediated NF-κB activation facilitates apoptosis in monocytes [87, 92]. Deviant NF-κB mediated inhibition of apoptosis might be involved in the initiation of atherosclerosis [87, 93–95].
In atherosclerotic plaques, the secretion of MMP-1, -3 and − 9, induces the destruction of the ECM and the loss of fibrous cap integrity, by reduction of collagen protein and might be important in plaque rupture; this release process is regulated by NF-κB [47, 96]. However, the types of MMPs might be different in various cell type and stimulus [72, 97, 98]. Following the inhibition of NF-κB, decreased MMP-1 production in response to of CD40L stimulation has been identified in healthy human macrophages. In addition, inhibition of NF-κB reduces MMP-1 and MMP-3 expression in Cholesterol-Feeding rabbits. Ox-LDL stimulation in macrophages promote the expression MMP-9 with upregulated activation of NF-κB [72, 97].
3.2 Myocardial infarction
Rupture of the coronary atherosclerotic plaque results in localized clot formation and subsequently myocardial infarction. Clot may spontaneously resolve or may be therapeutically dissolved. Unfortunately, reperfusion also results in the phenomenon of reperfusion injury. NF-κB plays a critical role in tissue responses to ischemia and reperfusion including inflammation, regional cardiomyocyte death and myocardial infarction. TNFR and TLR-mediated NF-κB activation are induced following ischemia/reperfusion. Moreover, hypoxia downregulates the activity of PHD1 (prolyl hydroxylase 1) and enhanced IKKβ expression as well as phosphorylation of IκBα for NF-κB activation following Ischemia [100, 101] (Fig. 4). Hypoxia also induces the expression of HIF1 (hypoxia-inducible factor 1) which also increases the expression of NF-κB subunits . Negative regulator of the NF-κB including redox-sensitive enzymes is inhibited and NF-κB is induced in response to ROS generation. Myocardial ischemia/reperfusion induce NF-κB activation in several cell types including ECs and resident immune cells in the heart. The production of pro-inflammatory molecules, including the adhesion proteins ICAM-1 and P-selectin, in these cells facilitates the migration of leukocyte to the infarct area .
NF-κB activation (p50/p65) with elevated expression of ICAM-1, TNF-α and IL-1β has been characterized in human atrial tissue derived from patients following myocardial ischemia/reperfusion. In vivo studies have shown that inhibiting NF-κB by pharmacological inhibitors or decoy oligonucleotides suppresses myocardialinjury following ischemia [104–106]. Additionally, loss of NF-κB1 also leads to improved cardiac function and lower mortality after myocardial infarction .
Similar to its effect in cell survival/apoptosis, NF-κB also exerts protective function following myocardial ischemia/reperfusion. For example, in a mouse myocardial infarction model, cardiomyocytes are protected by the expression of cytoprotective genes such as c-IAP1 and Bcl-2 induced by NF-κB activation .
3.3 Heart failure
Long-term ischemia following myocardial infarction promotes associated with cardiomyocyte apoptosis resulting in cardiac failure . Several clinical studies have found a strong link between NF-κB activation and heart failure. Failed human hearts contain activated forms of NF-κB [110, 111]. Improved cardiac function with decreased cardiac NF-κB activity was characterized in patients that received left ventricular assist devices . Conditions like hypertension result in cardiac hypertrophy- which is associated with KF-kb activation; however, the rhe role of NF-κB component p50 in cardiac hypertrophy is controversial. One study showed that loss of NF-κB led to a reduced cardiac hypertrophy (Fig. 4), However, another study showed that p50 deficiency enhanced cardiac dysfunction following myocardial infarction. The mechanism of discrepancy between the results of these two studies is not clear. However, p50 deficiency mice display reduced cardiac hypertrophy in response to TNF-α and Ang II, suggesting that NF-κB might be a positive regulator of hypertrophy [107, 113, 114].
The In vitro investigations also showed that Ang II facilitated IκB degradation, as well as p65 nuclear translocation and transcriptional activity in cardiomyocytes [115, 116]. Cardiac-specific overexpression of a non-degradable form of IκBα in mice attenuates cardiac hypertrophy phenotype and facilitates heart failure in response to Ang II and isoproterenol infusion [117, 118]. Several other studies have showed the protective effect of NF-κB in mice. Conditional deletion of NEMO in heart blocks NF-κB Activation and the mice showed enlargement of left atrium and eccentric hypertrophy. Moreover, the heart function was also significantly impaired. In another investigation, cardiac-specific IKKβ-deficient mice exhibited normal heart morphology and function. However, heart failure including cardiac dilation and dysfunction was observed in these mice under acute pressure overload [119, 120]. Channeling the mice with antioxidants reversed these phenotypes, indicating that NF-κB may perform its protective effect against cardiomyopathy by the induction of its downstream antioxidant genes.