Histone deacetylases (HDACs) are a superfamily of enzymes that catalyze the removal of acetyl functional groups from lysine residues of histone and non-histone proteins. There are 18 mammalian HDACs, which are classified into four classes based on the primary homology with yeast HDACs. Among these groups, Class I and II HDACs play a major role in lysine deacetylation of the N-terminal histone tails. In mammals, HDACs play a pivotal role in the regulation of gene transcription, cell growth, survival, and proliferation. HDACs regulate the expression of inflammatory genes, as evidenced by the potent anti-inflammatory activity of pan-HDAC inhibitors, which were implicated in several pathophysiologic states in the inflammation process. However, it is unclear how each of the 18 HDAC proteins specifically contributes to the inflammatory gene expression. It is firmly established that inflammation and its inability to converge are central mechanisms in the pathogenesis of several cardiovascular diseases (CVDs). Emerging evidence supports the hypothesis that several different pro-inflammatory cytokines regulated by HDACs are associated with various CVDs. Based on this hypothesis, the potential for the treatment of CVDs with HDAC inhibitors has recently begun to attract attention. In this review, we will briefly discuss (1) pathophysiology of inflammation in cardiovascular disease, (2) the function of HDACs in the regulation of atherosclerosis and cardiovascular diseases, and (3) the possible therapeutic implications of HDAC inhibitors in cardiovascular diseases. Recent studies reveal that histone deacetylase contributes critically to mediating the pathophysiology of inflammation in cardiovascular disease. HDACs are also recognized as one of the major mechanisms in the regulation of inflammation and cardiovascular function. HDACs show promise in developing potential therapeutic implications of HDAC inhibitors in cardiovascular and inflammatory diseases.
Irisin, a cleaved product of the fibronectin type III domain containing protein-5, is produced in the muscle tissue, which plays an important role in modulating insulin resistance. However, it remains unknown if irisin provides a protective effect against the detrimental outcomes of hemorrhage. Hemorrhages were simulated in male CD-1 mice to achieve a mean arterial blood pressure of 35–45 mmHg, followed by resuscitation. Irisin (50 ng/kg) and the vehicle (saline) were administrated at the start of resuscitation. Cardiac function was assessed by echocardiography, and hemodynamics were measured through femoral artery catheterization. A glucose tolerance test was used to evaluate insulin sensitivity. An enzyme-linked immunosorbent assay was performed to detect inflammatory factors in the muscles and blood serum. Western blot was carried out to assess the irisin production in skeletal muscles. Histological analyses were used to determine tissue damage and active-caspase 3 apoptotic signals. The hemorrhage suppressed cardiac performance, as indicated by a reduced ejection fraction and fractional shortening, which was accompanied by enhanced insulin resistance and hyperinsulinemia. Furthermore, the hemorrhage resulted in a marked decrease in irisin and an increase in the production of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). Additionally, the hemorrhage caused marked edema, inflammatory cell infiltration and active-caspase 3 positive signals in skeletal muscles and cardiac muscles. Irisin treatment led to a significant improvement in the cardiac function of animals exposed to a hemorrhage. In addition, irisin treatment improved insulin sensitivity, which is consistent with the suppressed inflammatory cytokine secretion elicited by hemorrhages. Furthermore, hemorrhage-induced tissue edema, inflammatory cell infiltration, and active-caspase 3 positive signaling were attenuated by irisin treatment. The results suggest that irisin protects against damage from a hemorrhage through the modulation of insulin sensitivity.
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