br Regulation of HO expression under conditions

Regulation of HO-1 expression under conditions of ischemic cardiac damage Heart is a vital organ with high metabolic demand, rich in mitochondria and it is very vulnerable to oxidative damage [85]. Disruption in coronary blood flow following MI leads to hypoxia (a reduction in the amount of available oxygen) which produces excessive amounts of free radicals and causes ischemic heart disease. If the damage in the ischemic muscle is not repaired, a chronic inflammatory response is set in motion. Chronic inflammation is the hallmark of the ischemic heart disease and is associated with increased oxidative stress and enhanced risk of HF development [86]. Several transcription factors activated under these conditions can upregulate HO-1 and, in fact, the expression of HO-1 is regulated mainly at the level of transcription [11,87,88]. There is a number of transcription factors Parathyroid hormone (1-34) (human) located in and upstream of the HO-1 promoter, including nuclear factor E2-related factor-2 (Nrf2), AP-1, and NFκB and their binding activates HO-1 transcription [89]. The HO-1 promoter contains also multiple other positive regulatory elements, such as stress-responsive element (StRE), cadmium-responsive element (CdRE), SMAD-binding element (SBE), AP-2, STATx and upstream stimulatory factor (USF) (reviewed in [11]). Although several transcription factors and signaling cascades are involved in HO-1 regulation, there are two main pathways identified in monocytes and macrophages. One is the already mentioned IL-10/HO-1 axis and the other – Nrf2/Bach1 system. Nrf2 is one of the key activators of genes involved in the antioxidative response, such as glutathione S-transferase (GST), γ-glutamylcysteine synthetase (γ GCS) and HO-1 [90]. With no stress stimuli, Nrf2 is accumulated in the cytosol, bound to Kelch-like ECH-associated protein-1 (Keap1). The protein partner halts Nrf2 translocation to the nucleus and directs it to ubiquitin ligase complex containing Cul3. This results in destining of Nrf2 for proteasomal degradation through conjugation of ubiquitin [91]. However, multiple cysteine residues of Keap1 are prone to oxidative modifications [92], leading to conformational changes of Keap1 and release of Nrf2 and its nuclear translocation [93]. Then, in the nucleus, Nrf2 binds to the small Maf protein and activates antioxidant response element (ARE), inducing expression of HO-1 [91] (Fig. 3). On the other hand, heme-regulated transcription repressor Bach1 binds Maf proteins and thus represses HO-1 via Maf response element (MARE). In this way, Bach1 also competes with Nrf2 for binding of Maf proteins [94]. Interestingly, heme can be bound by Bach1 with high affinity and may restrict the interaction of Bach1 with MARE [95] (Fig. 3). Thus, heme abolishes Bach1-mediated repression of HO-1 transcription. Importantly, numerous data indicate that HO-1 induced through Nrf2/ARE signaling pathway (either pharmacologically or genetically) confers tissue protection via decreasing oxidative stress and inflammation (reviewed in: [96]]. This may be useful in the clinical perspective. Another aspect of regulation of HO-1 expression in human cells is (GT)n dinucleotide length polymorphism of the promoter. Amongst human population, both basal and induced levels of HO-1 may vary. The human HO-1 promoter contains from 12 to 40 GT repeats, located approximately 250 bp upstream of the site where transcription of the gene starts (reviewed in: [97]). The most frequently described variants contain 23 and 30 repeats in different study populations (reviewed in: [97]). The more (GT)n repeats are found in the promoter, the more HO-1 expression is decreased [98]. Such a variant found in monocytes is associated with higher risk of arterial hypertension and decreased cumulative survival [79].
Spatiotemporal kinetics of monocyte/macrophage infiltration of heart after myocardial infarction Shortly after MI, different cells participate in the development of sterile inflammation (in absence of pathogens) in affected tissue. Cardiac macrophages residing in the myocardium provide a primary innate immune response triggered by activation of PRRs by DAMPs [99]. PRRs further activate IRF-, NFκB- and AP-1-signalling pathways and evoke production of interferons and proinflammatory cytokines in the injured heart [99]. Interestingly, very recently a novel PRR – cGAS (cyclic GMP-AMP synthase) sensing cytosolic DNA, has been identified as being potently activated in macrophages following MI. Such cGAS activation triggers STING (stimulator of interferon genes) cascade and promotes the transformation of macrophages toward inflammatory M1-like phenotype [100]. Inactivation of the pathway leads to change of macrophage polarization toward M2-like, reparative phenotype, improving wound healing and angiogenesis, as well as decreasing pathological cardiac remodeling, preventing ventricular rupture, and markedly enhanced survival after MI [100].