While the mechanisms by which ALDH

While the mechanisms by which ALDH2 regulates cardiac responses to pathological stress remain unclear, the capillary rarefaction found in pressure-overloaded ALDH2 Tg hearts provides potential clues. Loss of capillary density and diminished endothelial function occur in pathological hypertrophy [46], [47], [48] and have been suggested to play a causal role in idiopathic dilated cardiomyopathy [49] and heart failure with preserved ejection fraction [50], [51]. Interestingly, reactive products normally detoxified by ALDH2, such as HNE, can promote angiogenesis and augment microvessel density in other tissues [52], [53], [54]. Thus, it makes sense that HNE may be important for regulating capillary density in the heart as well. Interestingly, compared with corresponding NTg mice, Tbx3—a strong inducer of angiogenesis in the context of cancer [35]—was lower in pressure-overloaded ALDH2 Tg hearts. Additional studies will be required to discern how ALDH2 and the products it detoxifies influence myocardial angiogenesis. The fact that, in the context of pressure overload, ALDH2-overexpressing hearts showed higher catalase levels suggests a potential role of aldehyde dehydrogenase activity in modulating the detoxification of other Amikacin of reactive species. Catalase, which catalyzes the reduction of hydrogen peroxide, is upregulated in end-stage human heart failure [43]. Generally, catalase is considered to be a protective enzyme in the context of cardiomyopathy [55], [56], [57], [58], [59]. It is possible that augmentation of ALDH2 and other classes of antioxidant enzymes such as catalase diminish the hormetic responses known to protect against tissue injury and dysfunction [14], [19], [60]. Whereas catalase was elevated in ALDH2 Tg hearts, HO-1 expression was lower. Because HO-1 is protective in the context of heart failure [61], the lower levels of HO-1 may also contribute to the worsened pathological hypertrophy observed in pressure-overloaded ALDH2 Tg hearts. Furthermore, it is possible that the imbalanced redox landscape caused by overexpression of ALDH2 leads to a form of reductive stress that could worsen cardiac pathology, as suggested by previous studies [62], [63], [64]. There are several limitations to our study. Foremost is the dramatically elevated levels of ALDH2 in transgenic hearts. The high levels of ALDH2 expression led to its higher abundance not only in mitochondria, but in the cytosol as well, which potentially obfuscates data interpretation. Although results of our activity assays suggest > 100-fold higher ALDH2 enzyme detoxification capacity in the heart, it is unlikely that the enzyme is as active in vivo as measured in vitro, where saturating substrate and cofactor conditions and optimal pH (8.8) for ALDH2 activity are maintained. Indeed, the levels of protein-HNE adducts, while trending toward diminished abundance, were not remarkably different in ALDH2 Tg TAC hearts compared with NTg counterparts. Nevertheless, coherence of our finding with several other studies showing worsened hypertrophy in ALDH2-overexpressing models as well as diminished hypertrophy in ALDH2 knockout models [15], [16], [17] supports the idea that ALDH2 downregulation is not necessarily maladaptive under conditions of pressure overload. Another limitation is the lack of a clear mechanism for how ALDH2 affects pathological responses to pressure overload. It appears that ALDH2 overexpression not only augments cardiac hypertrophy, but it diminishes capillary density and remodels antioxidant enzyme expression as well. Further studies would be required to understand whether such changes relate causally to one another and to determine their relative contribution to pathological hypertrophy in this model.
Acknowledgements
Introduction Molecular chaperones are proteins that facilitate other newly synthesized or denaturated proteins to stabilize and/or to fold to their native, functional structures (Hartl et al., 2011; Hartl and Hayer-Hartl, 2009). Proper protein function is a key element of cellular homeostasis and crucially important to cells for coping with environmental or intrinsic stress (Morimoto and Cuervo, 2014). It is known that oxidative stress is a common cause of cellular proteotoxicity since oxidation of proteins results in their structural disruption and consequently in the formation of inactive, aggregation-prone intermediates (Mirzaei and Regnier, 2006; Niforou et al., 2014; Trougakos et al., 2013).