NF-κB, A Potential Therapeutic Target in Cardiovascular Diseases

Abstract

Cardiovascular diseases (CVDs) are the leading cause of death globally. Atherosclerosis is the basis of major CVDs -myocardial ischemia, heart failure and stroke. Among numerous functional molecules, the transcription factor nuclear factor κB (NF-κB) has been linked to downstream target genes involved in atherosclerosis. The activation of NF-κB family and its downstream target genes in response to environmental and cellular stress, hypoxia and ischemia initiate different pathological events such as innate and adaptive immunity, and cell survival, differentiation and proliferation. Thus, NF-κB is a potential therapeutic target in the treatment of atherosclerosis and related CVDs. Several biologics and small molecules as well as peptide/proteins have been shown to regulate NF-κB dependent signaling pathways. In this review, we will focus on the function of NF-κB in CVDs and the role of NF-κB inhibitors in the treatment of CVDs. IntroductionCardiovascular diseases (CVDs) are the leading causes of death in the Western hemisphere and rapidly becoming so in the developing world. While the major risk factors leading to CVDs have been well addressed and targeted to prevent and treat CVDs, the precise steps and molecular mechanism leading to atherogenesis and its major manifestations are yet being described. Here we focus on nuclear-factor kappa beta (NF-κB) as an important transcription factors involved in several steps in the development of CVDs. N F-κB familyMany genes contain a nearly palindromic DNA sequence with a consensus of 50-GGGRNWYYCC-30 (N, any base; R, purine; W, adenine or thymine; Y, pyrimidine), which is termed κB [1]. The elements in enhancers or promoters of these genes can be recognized by a class of proteins such as NF-κB that subsequently initiate the transcription of these genes. NF-κB in mammals is a family of ve related proteins: RelAIp65, RelB, c-Rel, NF-κB1 (p50 and its precursor p105), and NF-κB2 (p52 and its precursor p100) (Fig. 1-part I) [2]. These subunits share N-terminal Rel homology domain (RHD) with the v-Rel oncogene and form dimers that can positively or negatively regulate gene expression. RHD is responsible for homo-and heterodimerization as well as for sequence-speci c DNA binding to κB sites. NF-κB family contains two subfamilies: p65, RelB and c-Rel containing a C-terminal transcriptional transactivation domain (TAD) which confers the ability to promote gene expression; p50 and p52 lacking a TAD have a dual role (Fig. 1-part I). Homodimers of p50 and p52 are thought to repress transcription through competing with transcriptionally active dimers to bind to their DNA targets. While they are bound to p65, RelB or c-Rel as part of a heterodimer, p50 and p52 can promote transcription. RelB is unique in that it also contains an N-terminal leucine zipper (LZ) region that needs to work with its TAD to be fully functional. Since RelB has only been veri ed to form dimers with p50 and p52, there are only 12 dimers existing in cells. The C-terminal death domain (DD) in C-terminal half of p10...

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