PRE-CLINICAL RESEARCH: EDITORIAL COMMENT
Lessons From the Besotted Heart*
Joel S. Karliner, MD*
Cardiology Section, VA Medical Center, San Francisco, California
* Reprint requests and correspondence: Dr. Joel S. Karliner, Cardiology Section, VA Medical Center, 4150 Clement Street, San Francisco, California 94121 (Email: joel.karliner{at}va.gov).
Key Words: ethanol • ALDH2 • myocardial dysfunction • Akt • protein phosphatase
In poison there is no physic.
—Shakespeare, King Henry IV, Part II, Act 1, Scene i (1)
The fox barks not when he would steal the lamb.
—Shakespeare, King Henry VI, Part II, Act III, Scene i (2)
Ethanol ingestion has both favorable and deleterious consequences. Viewed as a drug that affects the cardiovascular system, chronic ethanol use in small amounts is cardioprotective, both in humans and in animals (3). It has been suggested that ethanol may activate pro-survival signaling pathways that are also seen during acute cardioprotection initiated by ischemic pre-conditioning (4,5). The acute effects of ethanol on the heart appear to be dose-dependent, with lower concentrations inducing cardioprotection (6) and larger doses causing cardiac damage (7). Cardiotoxicity resulting from excessive alcohol ingestion is thought to be at least in part mediated by generation of its metabolite acetaldehyde (8).
Previous data have indicated a protective role of the mitochondrial isoform of aldehyde dehydrogenase (ALDH2) against acetaldehyde or ethanol-induced myocardial injury (9). In a report appearing in this issue of the Journal, Ma et al. (7) have examined the hypothesis that overexpression of ALDH2 can mitigate myocardial injury induced by a substantial intraperitoneal dose (3 mg/kg) of ethanol given to mice transgenic for ALDH2 and their wild-type littermates. In the hearts of transgenic animals compared with wild-type littermates after ethanol injection, they found reduced levels of acetaldehyde and protein carbonyl formation. There was also less reduction in cardiac contractile function, and preserved phosphorylation of Akt and AMP-activated protein kinase (AMPK) associated with dampened phosphorylase activity. These findings were associated with restoration of depressed phosphorylation of forkhead transcription factor 3 of the O subgroup (Foxo3) at 2 sites, Thr32 and Ser413. In the ALDH2 transgenic hearts, caspase-3 activity, a marker of apoptosis, was also significantly attenuated as was the fall in mitochondrial membrane potential.
The above observations shed additional light on events that occur during acute ethanol-induced cardiotoxicity. How these mechanisms interact in the ALDH2 mouse heart needs to be explored. Thus, the relation between ALDH2 and the increase in PP2A and PP2C phosphatase activity, which is the link between the reduction in phosphorylation of Akt, AMPK, and depression of Foxo3, remains mysterious. Similarly, how Foxo3 affects mitochondrial function is not elucidated by these data, and is a topic for future study.
Nevertheless, the work of Ma et al. (7) illuminates an even larger issue, that is, the effects of both ethanol and other pharmacologic activation of ALDH2 on cardioprotection during ischemia/reperfusion injury. In a recent study, Churchill et al. (6) reported in a rat model of acute myocardial infarction that a lower concentration of ethanol (0.5 mg/kg) than that used by Ma et al. (7) reduced infarct size. The ethanol had to be given 60 min before coronary artery ligation in order to promote translocation of epsilon-PKC to cardiac mitochondria where the enzyme bound ALDH2, resulting in a decline of toxic aldehydes manifested as a reduction in 4-hydroxy-2-nonenal adducts (6). In this connection, it is important to note that a recent landmark study described a small molecule activator of ALDH2 (called Alda-1) that also reduced infarct size by 60%, most likely through the inhibitory effect of ALDH2 on the formation of cytotoxic aldehydes (10).
Another important aspect of the report of Ma et al. (7) is the observation that Foxo3 may have a role in protecting the myocardium from injury. A member of a large and complex family of nuclear transcription factors, Foxo3 has been implicated in the inhibition of apoptosis and in activation of manganese superoxide dismutase (11), but until recently, little attention has been paid to the role of Foxo factors in myocardial ischemia/reperfusion injury. Recent studies have begun to fill this gap. Thus, bromelain, a proteolytic enzyme extracted from the stem of the pineapple, induced cardioprotection against ischemia/reperfusion injury in rat myocardium through the Akt/Foxo pathway (12). Similarly, the white wine component, n-tyrosol [2-(-hydroxyphenyl)ethanol] uses the Akt/Foxo3a pathway to mediate cardioprotection (13). Forkhead transcription factors also coordinate expression of myocardial KATP channel subunits and energy metabolism by regulating genes involved in balancing glycolysis and beta-oxidation (14).
In summary, there appears to be an emerging consensus regarding the central importance of toxic aldehydes and of their modulation by ALDH2 in acute myocardial injury (Fig. 1). Foxo factors also appear to be important in alleviating acute cardiac damage, but the precise targets of the various Foxo factors and whether they undertake functions in addition to their actions as transcription factors during acute myocardial injury remain to be determined. Thus, the work of Ma et al. (7) calls attention to new threads in the skein of cardioprotective signaling, an ever-enlarging tapestry of intricate complexity.
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Figure 1 Responses to Ethanol Ingestion Depend on Ethanol Levels
Depicted in the left panel is the "sad" heart, which is acutely depressed by high ethanol levels as well as by ischemia/reperfusion injury. Toxic aldehydes and reactive oxygen species are produced that among other effects, reduce prosurvival signals such as those transduced by Akt, AMP-activated protein kinase, and Foxo3. In the "happy" heart on the right, these adverse responses can be prevented by overexpression of aldehyde dehydrogenase 2 or by a small molecule activator of this enzyme, Alda-1. See the text for details. Figure illustration by Rob Flewell. Alda-1 = small molecule activator of aldehyde dehydrogenase 2; ALDH2 = aldehyde dehydrogenase 2; ETOH = ethanol; FOXO3 = forkhead transcription factor of the O subtype; IPC = ischemic pre-conditioning; pAkt = phosphorylated prosurvival serine-threonine kinase; pAMPK = phosphorylated adenosine monophosphate kinase; PKC = protein kinase C epsilon; PP2 A and C = protein phosphatase A and C; ROS = reactive oxygen species; TG = transgenic.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Shakespeare, King Henry IV, Part II, Act 1, Scene i.2. Shakespeare, King Henry VI, Part II, Act III, Scene i. 3. Collins MA, Neafsey EJ, Mukamal KJ, et al. Alcohol in moderation, cardioprotection, and neuroprotection: epidemiological considerations and mechanistic studies Alcohol Clin Exp Res 2009;33:206-219.[CrossRef][Web of Science][Medline] 4. Miyamae M, Diamond I, Weiner MW, Camacho SA, Figueredo VM. Regular alcohol consumption mimics cardiac preconditioning by protecting against ischemia-reperfusion injury Proc Natl Acad Sci U S A 1997;94:3225-3239. 5. Zhou H-A, Karliner JS, Gray MO. Moderate alcohol consumption induces sustained cardiac protection by activating protein kinase C and Akt Amer J Physiol Heart Circ Physiol 2002;283:H165-H175. 6. Churchill EN, Disatnik M-H, Mochly-Rosen D. Time-dependent and ethanol-induced cardiac protection from ischemia mediated by mitochondrial translocation of PKC and activation of aldehyde dehydrogenase 2 J Mol Cell Cardiol 2009;46:278-284.[CrossRef][Web of Science][Medline] 7. Ma H, Li J, Gao F, Ren J. Aldehyde dehydrogenase 2 ameliorates acute cardiac toxicity of ethanol: role of protein phosphatase and forkhead transcription factor J Am Coll Cardiol 2009;54:2187-2196.[Abstract/Free Full Text] 8. Ren J, Wold LE. Mechanisms of alcoholic heart disease Therap Adv Cardiovasc Dis 2008;2:497-506.[CrossRef] 9. Li SY, Gomelsky M, Duan J, et al. Overexpression of aldehyde dehydrogenase-2 (ALDH2) transgene prevents acetaldehyde-induced cell injury in human umbilical vein endothelial cells: role of ERK and p38 mitogen activated protein kinase J Biol Chem 2004;279:11244-11252.[Abstract/Free Full Text] 10. Chen C-H, Budas GR, Churchill EN, et al. Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart Science 2008;321:1493-1495.[Abstract/Free Full Text] 11. Papanicolaou KN, Izumiya Y, Walsh K. Forkhead transcription factors and cardiovascular biology Circ Res 2008;102:16-31.[Abstract/Free Full Text] 12. Juhasz B, Thirunavukkarasu M, Pant R, et al. Bromelain induces cardioprotection against ischemia-reperfusion injury through Akt/FOXO pathway in rat myocardium Amer J Physiol Heart Circ Physiol 2009;294:H1365-H1370. 13. Samuel SM, Thirunavukkarasu M, Penumathsa SV, Paul D, Maujlik N. AktFOXO3a/SIRT1-mediated cardioprotection by n-tyrosol against ischemic stress in rat in vivo model of myocardial infarction: switching gears toward survival and longevity J Agric Food Chem 2008;56:9692-9698.[CrossRef][Web of Science][Medline] 14. Philip-Couderc P, Tavares NI, Roatti A, Lerch R, Montessuit C, Baerschi AJ. Forkhead transcription factors coordinate expression of myocardial KATP channel subunits and energy metabolism Circ Res 2008;102:e20-e35.[Abstract/Free Full Text]
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