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Although several studies indicate that ALDH protects
Although several studies indicate that ALDH2 protects the heart from injury and maladaptive remodeling (reviewed in [11], [12], [13]), accumulating evidence indicates that deficiency of the enzyme could be protective as well. For example, mice expressing the defective Aldh2*2 mutation show lower aldehyde detoxification capacity yet are protected against ischemia-reperfusion injury [14]. Moreover, overexpression of ALDH2 worsens aging-induced cardiac hypertrophy and dysfunction and shortens lifespan [15], [16], and deficiency of ALDH2 prevents cardiac hypertrophy caused by pressure overload [17]. These studies suggest that diminishment of mitochondrial aldehyde dehydrogenase capacity may actually confer beneficial consequences, redolent of the hormetic effects of mitochondrial reactive species on survival and longevity [18], [19], [20] and the critical role of oxidants in tissue WM-8014 to injury [21]. Nevertheless, it remains unclear whether the decrease in ALDH2 activity occurring in heart failure is deleterious or adaptive.
Methods
Results
Discussion
The abundance of several aldehyde-detoxifying enzymes is lower in the failing heart. In particular, ALDH2 is downregulated in both the infarcted and pressure-overloaded heart [8], [9], [10]. Nevertheless, it remains unclear whether decreases in ALDH2 expression are beneficial or deleterious in the context of pathological stress. In this study, we tested the hypothesis that enforcing ALDH2 levels in the pressure-overloaded heart improves cardiac function and remodeling. Similar to previous findings, we found that ALDH2 abundance and activity were lower in hearts subjected to pressure overload; however, not only was cardiac-specific overexpression of ALDH2 insufficient to prevent cardiac dysfunction due to pressure overload, it augmented the hypertrophic response and diminished capillary density. These changes were associated with altered expression of the antioxidant enzymes catalase and HO-1. Our findings suggest that increasing ALDH2 expression or activity may not be beneficial in all contexts of heart failure and imply that the downregulation of ALDH2 may be an adaptive response that controls the redox landscape, permits angiogenesis, and limits hypertrophy under conditions of pressure overload.
Our findings are surprising given the relatively large number of studies that attest to a beneficial role of ALDH2 in cardiac pathology. Seminal studies showed that small molecule activation of ALDH2 diminishes ischemic damage to the heart [36], [37], [38]. Later studies demonstrated that whole-body ALDH2 deletion worsens injury due to ischemia-reperfusion, whereas whole-body ALDH2 overexpression diminishes injury [39]; other studies appear to confirm the protective effect of ALDH2 in the acutely injured heart (e.g., [40], [41], [42]). Nevertheless, mice expressing Aldh2*2, which is a single nucleotide polymorphism that lowers ALDH2 activity, were found to be protected against cardiac ischemic injury [3], [14], which suggests a potential Janus face of ALDH2.
A beneficial role of ALDH2 is less clear in the context of cardiac hypertrophy. Whereas ALDH2 has been suggested to be protective in alcohol-induced cardiomyopathy [43], myocardial infarction-induced heart failure [9], [44] and pressure overload-induced cardiac dysfunction [10], a nearly equivalent level of evidence exists for deleterious effects of ALDH2. General overexpression of ALDH2 was found not only to promote cardiac hypertrophy and contractile dysfunction in aged mice [15], but to shorten lifespan and promote cardiac aging as well [16]. Moreover, deletion of ALDH2 was shown to prevent cardiac hypertrophy caused by pressure overload [17]. Similarly, cardiac-specific overexpression of aldose reductase, which can reduce aldehydes such as HNE to their less reactive alcohols, causes cardiac hypertrophy and contractile dysfunction in aged mice [45]. These findings suggest that the abundance of ALDH2 and other aldehyde-detoxifying enzymes may modulate hypertrophic programs in the heart. Our results showing increased expression of a molecular marker of hypertrophy (Nppb) and an exaggerated hypertrophic response to TAC in ALDH2 Tg mice appear consistent with this idea.