High-mobility group box 1 protein, angiotensins, ACE2, and target organ damage.

Abstract

High-mobility group box 1 (HMGB1) protein is an important chromatin protein. In the nucleus, HMGB1 interacts with nucleosomes, transcription factors, and histones. The nuclear protein organizes the DNA and regulates transcription [1]. After binding to DNA, HMGB1 bends DNA, thereby facilitating the binding of other proteins. HMGB1 supports transcription of many genes in interactions with numerous transcription factors. HMGB1 also interacts with nucleosomes to loosen packed DNA and remodel the chromatin. Contact with core histones changes the structure of nucleosomes. The presence of HMGB1 in the nucleus depends on posttranslational modifications. When the protein is not acetylated, it remains within the nucleus; however, hyper acetylation on lysine residues causes HMGB1 to translocate into the cytosol [2]. Here, HMGB1 assumes quite different roles. Immune cells can secrete the protein. For instance, dendritic cells, macrophages, and monocytes secrete HMGB1 in response to cytokines to mediate inflammation. The mechanism of inflammation and damage is HMGB1 binding to receptor for advanced glycation end products (RAGE), Toll-like receptor 2 (TLR2), and TLR4 to mediate nuclear factor kappaB (NF-κB) activation [3]. This state-of-affairs positions HMGB1 at the intersection of sterile and infectious inflammatory responses [4, 5]. The multifaceted activities of HMGB1 (Fig. 1) have been reviewed (5). Evidence has been presented that angiotensinconverting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) can reduce secretion of HMGB1 [6, 7]. This observation would be consistent with possible interactions between HMGB1 and the renin-angiotensin system. The angiotensin-converting enzyme (ACE) is a matrix metalloproteinase cleaving decapeptide angiotensin (Ang) I to the octapeptide Ang II. ACE, and its orthologs possess 2 peptidase M2 domains. ACE2, discovered more recently but probably a teleological older enzyme, and its orthologs possess a single peptidase M2 domain. Ang I and II can be cleaved by ACE2 into nonapeptides (Ang1–9) and septapeptides (Ang1–7), respectively. The ACE2 protein also serves as a receptor for corona viruses. The ACE metalloproteinases have been around on the planet for a long time. Similar sequences are found in flies and even in bacteria, while renin first enters the scene at the bony-fish level [8]. The generation of Ang1–7 by ACE2 is said to have a vascular protective function. Nevertheless, ACE2 targeting in mice resulted in mixed messages. There have been at least three lines of ACE2 knockout mice reported by various investigators [9]. Interestingly, there are significant differences in the phenotypes of these distinct lines, especially with regard to their cardiovascular physiology. ACE2 appears to have only modest effects on baseline cardiovascular functions and blood pressure control. These effects can be substantially modulated by genetic and, perhaps through environmental factors. In contrast, the activity of ACE2 may have more profound effects on susceptibility to pathological states, such as hypertension and cardiac hypertrophy. In this issue of J Mol Med, Qi et al. [10] studied mice harboring a FLAG-tagged mouse ACE2 gene * Friedrich C. Luft luft@charite.de