Cardiovascular disease: Enhanced protection of the heart

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Phosphorylation and activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) mimics the cardioprotective mechanism known as preconditioning that is induced by repetitive sub-lethal ischemic events.

Since the discovery of a cardioprotective mechanism known as preconditioning — induced by repetitive sub-lethal ischaemic events — there has been a search for agents that could mimic this effect and thereby limit damage caused by cardiac ischaemia. Writing in Science, Mochly-Rosen and colleagues report that activation of aldehyde dehydrogenase 2 (ALDH2) correlates with cardioprotection. They also describe a small-molecule activator of ALDH2 that can reduce infarct size by 60% when administered to rats before an ischaemic event.

Initial proteomic studies identified mitochondrial ALDH2 as the only protein for which phosphorylation status consistently correlated with cardioprotection in homogenates of ischaemic rat hearts preconditioned by treatment with ethanol or an activator of protein kinase C epsi (PKC epsi ). Further studies in intact rat hearts showed that ALDH2 activity — stimulated by alcohol or a PKC epsi agonist, or inhibited by a PKC epsi antagonist, cyanamide or nitroglycerin — correlated with a reduction in infarct size following ischaemia.

This correlation does not necessarily mean that ALDH2 activation is sufficient to induce cardioprotection. So, to clarify this issue, the authors used high-throughput screening to search for agonists of ALDH2 and identified N-(1,3-benzodioxal-5-methyl)-2,6-dichlorobenzamide (Alda-1) as one of the more potent agonists.

Alda-1 (at EC₅₀ of $sim$ 20 µM) conferred a 2.1-fold increase in ALDH2 activity over basal levels. Interestingly, it also activated ALDH2^*2 — a mutant form (E487K) that is common in those of East Asian origin, but which only has 1–5% of the catalytic activity of the wild-type form — by 11-fold.

Alda-1 was then tested in various ischaemia–reperfusion models. Notably, administration of Alda-1 into the left ventricle of rats before ischaemia resulted in a 60% reduction in infarct size.

Finally, the authors investigated the molecular basis of the cardioprotective effects of Alda-1, and provided evidence that removal of 4-hydroxynonenal (4HNE), a toxic aldehyde that accumulates during cardiac ischaemia, could be important. This aldehyde can inactivate ALDH2, and the authors showed that 4HNE-induced inactivation of ALDH2 was blocked by Alda-1, which increased the detoxification of 4HNE.

In summary, these data raise the possibility that pharmacological enhancement of ALDH2 activity might be beneficial for patients subjected to cardiac ischaemia — for example, during coronary bypass surgery. The ability of Alda-1 to rescue ALDH2^*2 activity suggests that patients with this mutant form might benefit especially from treatment with ALDH2 activators.

Man Tsuey Tse

References

Chen, C.-H. et al. Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science 321, 1493–1495 (2008) | Article | PubMed |