stavudine On the other hand after injury of the adult

On the other hand, after injury of the adult heart, inflammatory monocytes are abundantly recruited to damaged myocardium and they differentiate into monocyte-derived macrophages (MDMs). They have strong proinflammatory phenotype and very limited capacity to promote angiogenesis and cardiomyocyte proliferation. This loss of regenerative potential in the adult myocardium was also attributed to the loss of CCR2- and expansion of CCR2+ MDMs [118], as well as to the low proliferative capacity of adult cardiomyocytes, which do not possess regenerative potential like the neonatal ones. Proinflammatory monocytes and MDMs contribute to a loss of tissue-resident macrophages, augment monocyte and neutrophil infiltration and therefore impair LV recovery of the adult heart [118,122]. We have recently shown that in HO-1 deficient mice even 3 weeks following MI monocytosis in peripheral blood was present and populations of cardiac macrophages were strongly enriched in CD11c+ subsets [103] (Fig. 4). Macrophages expressing CD11c were previously reported to represent a classical proinflammatory phenotype and to efficiently produce IL-1β, TNF-α and IFN-γ [123].
Pharmacological and genetic manipulation of HO-1 expression in cardiac ischemia HO-1 is a meaningful player in governing cardiac homeostasis and following cardiac damage. HO-1 expression is strongly induced after MI [103], however, the endogenous induction seems to be either not strong enough or too late to fully pronounce actions of the protein. It was previously shown, that artificially increased levels of HO-1 after MI resulted in improved heart function and lowered infarct size, reduced apoptosis and inflammation [111,124,125]. Furthermore, high expression of HO-1 in atrial fibroblasts abrogated collagen production [126]. On the other hand, lack of HO-1 in vivo was associated with greater than in wild-type mice collagen deposition in atria in steady-state [126] and in LV after MI [103]. Due to high stavudine demand, cardiomyocytes depend on oxidative respiration [127] and contain numerous mitochondria, which occupy at least 30% of the cell volume [128]. Therefore, the cells contain lots of hemoproteins, such as cytochromes and Mb [129]. Thus, in these cells, heme management is substantial. It may indicate that HO-1 is very important for maintenance of cardiomyocyte homeostasis. It was suggested, that cells, such as cardiomyocytes, overexpressing HO-1 are better prepared for local excessive heme release from dying cells [130]. There are numerous studies demonstrating protective properties of high HO-1 level in cardiomyocytes. Delivery of exogenous HO-1 by gene therapy or activation of Nrf2/HO-1 pathway in stress conditions results in reduced cardiomyocyte apoptosis, better control of post-ischemic inflammation, prevents cardiac dysfunction and improves cardiac recovery following ischemic damage [111,124,125,131,132]. Also, it was demonstrated, that even the use of HO-1 activity product – CO improves cardiac remodeling and healing after MI [133]. Up to date, various studies have demonstrated significant protective properties of HO-1 in ischemia- or ischemia/reperfusion (I/R)-induced heart injury models. In mice exposed to I/R, heterozygous disruption of HO-1 gene resulted in an increase of infarct size, as well as reduced recovery of LV function [134]. We have recently shown that even more pronounced effects could be observed for HO-1 knock-out animals, where MI induction led to severe impairment of heart function [103]. In such situation, lack of HO-1 contributes to adverse late LV remodelling associated with elevated myocardial infiltration of MDMs [103] (Fig. 5). On the other hand, cardiac-restricted HO-1 overexpression, for both ex vivo and in vivo experiments involving I/R injury, showed a considerable decrease of the infarct region, improved recovery of heart function together with reduced inflammatory cell infiltration and apoptosis [124]. These results create a rationale for further investigation of HO-1 as a therapeutic agent, especially in MI models.