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Journal of Molecular and Cellular Cardiology 44 (2008) 979–982www.elsevier.com/locate/yjmcc

Editorial

Alcoholic cardiomyopathy: Acetaldehyde, insulininsensitization and ER stress

1. Alcohol and heart disease Both ethanol and acetaldehyde have toxic effects on the heart:

Nearly 1 out of every 3 alcoholics display some forms ofcardiomyopathic problems including hypertrophied heart, myofi-brillary disruption, reduced contractility, decreased ejectionfraction and stroke volume [1]. A number of theories have beenspeculated for the onset and development of alcoholic cardio-myopathy such as ethanol toxicity, reactive oxygen species (ROS)accumulation and oxidative stress, protein-aldehyde adducts,build-up of fatty acid ethyl esters, modification of lipoprotein andchange in neurohumoral or hormonal factors [2–4]. Despite thefact that these theories have offered a great deal of mechanismstowards alcohol-induced tissue damage, the validity of one theoryoften relies on the concept of another theory. As a result, none ofthese theories may be considered the ultimate cause for thepathogenesis of alcoholic cardiomyopathy observed in bothclinical and experimental settings. In this issue of JMCC, Li andRen [5] examined the impact of augmented acetaldehyde ex-posure following chronic alcohol intake on cardiac function andgeometry using a transgenic mouse model with cardiac-specificoverexpression of alcohol dehydrogenase (ADH). Followingchronic alcohol feeding in ADH and wild-type FVB mice, theseinvestigators found glucose intolerance, dampened cardiacglucose uptake, cardiac hypertrophy and contractile dysfunctionin alcohol-fed FVB mice. Interestingly, these defects, with theexception of whole body glucose tolerance, were significantlyexaggerated by the ADH transgene.

2. Acetaldehyde plays a key role in alcoholiccardiomyopathy: “acetaldehyde toxicity theory”

It is known that after absorption and passage through the liver,ethanol is distributed in the body water space and largelymetabolized in the liver to acetaldehyde by ADH in cytosol andcytochrome P450IIE1 in microsomes. Acetaldehyde is convertedby aldehyde dehydrogenases (ALDH) (especially the mitochon-drial ALDH2 isozyme) to acetate, which is excreted from the liverand metabolized by other organs. Although liver is the major sitefor ethanol oxidation, other organs including the heart alsoexpress ADH and ALDH2 enzymes and participate in ethanolmetabolism [6]. In addition to ethanol metabolism, acetaldehydecan also be generated through degradation of biologicalmolecules, e.g., lipid peroxidation [7].

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alcohol inhibits mitochondrial respiration and the activity ofenzymes in the tricarboxylic acid cycle, and interferes with bothmitochondrial calcium uptake and binding; Alcohol alsoprofoundly affects cardiac lipidmetabolism;Acetaldehyde dimin-ishes cardiac protein synthesis and inhibits calcium-activatedmyofibrillar ATPase. Therefore, it has been a controversial issuefor decades whether alcohol exerts its toxic effects directly on theheart or indirectly through its metabolite acetaldehyde, as stated insome of the early reviews [8–10].

The key role of acetaldehyde in alcoholic cardiomyopathyhas been appreciated by Epstein and Ren's groups [11–15]. Inthese studies transgenic overexpression of ADH to elevatecardiac exposure to acetaldehyde was used, and the authorsfound that ADH activity was increased by ~40-fold in the heartof ADH transgenic mice, which results in a 4–6-fold increase incardiac acetaldehyde production after alcohol ingestion [11,15].ADH transgene itself does not affect morphological, mechanicaland intracellular Ca2+ properties, indicating that the transgene isnot innately harmful. The authors demonstrated that both acuteand chronic alcohol administration promoted ethanol-inducedcardiac contractile depression and development of alcoholiccardiomyopathy [11,14,15]. Interestingly, ethanol-induced car-diac depressant effects were significantly exacerbated in cardio-myocytes from ADH mice [14]. Expression of mRNA in ANPand α-skeletal actin which serve as hypertrophic markers weremuch higher in alcohol consuming ADH mice compared withalcohol consuming FVBmice [11]. The more pronounced defectin ADH mice following alcohol consumption was associatedwith dampened intracellular Ca2+ release and sarcoplasmicreticulum (SR) Ca2+ load as well as enhanced lipid peroxidationand protein carbonyl [15]. An in vitro study also indicated thatthe ethanol-induced depression on cell shortening and intracel-lular Ca2+ was significantly augmented in ADH cardiomyo-cytes, the effect almost doubled that in WT myocytes.Pretreatment with the ADH inhibitor 4-methylpyrazole (4-MP)prevented the ethanol-induced inhibition, respectively, in theADH myocytes but not in WT myocytes [14]. These datasuggested that elevated cardiac acetaldehyde exposure due toenhanced ADH expression plays the critical role in the develop-ment of alcoholic cardiomyopathy.

To further support the “acetaldehyde toxicity theory” foralcoholic cardiomyopathy, overexpression of ALDH2was shown

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to alleviate acetaldehyde-induced cell injury in human umbilicalvein endothelial cells and human cardiac cells [16,17]. Althoughthere was little information regarding the effect of ALDH2 null onalcohol-induced cardiac damage under an in vivo condition,several studies have demonstrated increased oxidative damage inthe liver and peripheral tissues of ALDH2 knockout mice withacute or chronic exposure to alcohol or acetaldehyde [18–20].

Collectively, these studies implicated that ADH may exag-gerate whereas ALDH2 may attenuate alcohol-induced cardiacinjury, suggesting that enhanced acetaldehyde production isdetrimental whereas facilitated acetaldehyde breakdown may bebeneficial to alcoholic cardiomyopathy [21]. The study by Liand Ren in the current issue of JMCC has consolidated the“acetaldehyde toxicity theory” for alcoholic tissue injury [5]. Italso propels our understanding the mechanisms of alcoholiccardiomyopathy by providing the following new concepts.

3. Alcoholic impairment on insulin signaling in the heart

Epidemiological evidence has indicated that the relationshipbetween alcohol consumption and insulin sensitivity is either aninverted U-shape or a positive linear one [22,23]. Although lightto moderate alcohol intake seems to reduce cardiovascular riskthrough increased high density lipoprotein-cholesterol andinsulin sensitivity, the current recommendation set forth bythe American Heart Association and others to limit alcoholintake to no more than two drinks per day for men and one drinkper day for women appear justified but should be cautiouslypromoted [1]. In fact, chronic alcohol intake at levels beyondmoderate drinking has been associated with development ofinsulin resistance syndrome [22,24,25].

In a recent study from Li and Ren [26], reduced insulinsensitivity following chronic alcohol consumption in alcohol-induced brain damage was indicated. They found that chronicalcohol intake by feeding with a 4% alcohol diet for 16 weekssignificantly dampenedwhole body glucose tolerance, enhancedexpression of caspase-3 and mTOR, reduced p70s6k and 4E-BP1in mouse cerebral cortex. These data suggest that chronic alcoholintake may contribute to cerebral cortex dysfunction throughmechanisms related, at least in part, to dampened post insulinreceptor signaling at the levels of mTOR, p70s6k and 4E-BP1.Similarly, in cultured cell line chronic exposure to ethanol also ledto a disruption of insulin signaling via impaired phosphorylationof Akt at Thr308. This alteration was accompanied with a reduc-tion of nuclear SREBP accumulation and resulted in activation ofADH transcription [27]. However, it remains unclear whetherthis suppression of insulin signaling is really responsible for thecardiac effect of alcohol.

In the study reported in the current issue of JMCC [5], chronic(12 weeks) alcohol feeding led to glucose intolerance, dampenedcardiac glucose uptake, cardiac hypertrophy and contractiledysfunction in alcohol-fed FVB mice, which are in line withthe observation in the above studies [26,27]. These defects,however, with the exception of whole body glucose tolerancewere significantly exaggerated by the ADH transgene. Theirfurther evaluation of the receptor and post-receptor signalingrevealed depressed insulin-stimulated phosphorylation insulin

receptor (tyr1146) and IRS-1 (tyrosine) as well as enhanced serinephosphorylation of IRS-1 in cardiomyocytes from ethanol-fedmice. ADH augmented alcohol-induced effect of IRS-1 phos-phorylation (tyrosine/serine). Alcohol reduced phosphorylationof Akt and GSK-3β as well as GSK-3β expression and the effectwas exaggerated by ADH. These results should consolidate theexistence of whole body and cardiac insulin insensitivity fol-lowing chronic alcohol intake, suggesting that insulin resistancedirectly related to increased acetaldehyde may play an essentialrole in chronic alcohol intake-induced cardiac dysfunction.

4. Alcoholic ER stress and oxidative stress

The endoplasmic reticulum (ER) is a multifunctional organelleresponsible for the synthesis and folding of proteins as well ascalcium storage and signaling. Newly synthesized secretaryproteins translocate into the ER lumen and acquire their correctconformation prior to being exported to targeted cellularcompartments. When folding is not properly achieved, proteinsaccumulate in ER due to resident quality control machineries andthe terminallymisfolded proteins are ultimately degraded throughthe ER-associated degradation pathway. All these molecularmachines function in a coordinated fashion to restore and main-tain ER homeostasis. Perturbation of ER function triggers ERstress, which leads to unfolded protein response (UPR), inhibitionof protein synthesis, protein refolding and clearance of misfoldedproteins. ER stress-induced apoptosis has been implicated inthe pathogenesis of various diseases such as brain ischemia/reperfusion, neurodegeneration, diabetes and, most recently,cardiac infarction and heart failure. Three different classes ofER stress transducers have been identified namely inositol-requiring protein-1 (IRE1), the protein kinase RNA (PKR)-likeER kinase (PERK)-translation initiation factor eIF-2α pathwayand activating transcription factor-6 (ATF6). Each of the three ERstress transducers governs a distinct arm of ER stress-inducedunfolded protein response (UPR). Li and Ren [5] provided thefirst evidence to display up-regulation of IRE1 and eIF-2α, two ofthe major ER-resident transmembrane proteins sensing ER stress,in the hearts following chronic alcohol ingestion. This is sup-ported by their finding that alcohol intake significantly enhancedexpression of the UPR target pro-apoptotic protein gadd153, theinduction of which in the UPR is highly dependent upon thePERK/eIF-2α pathway [28,29]. It has been implicated thatgadd153may serve as amarker of PERK activity in theUPR [29].Their further observation revealed up-regulation of the ERchaperone GRP78 (also known as BiP) which directly interactswith all three ER stress sensors, PERK/eIF-2α, ATF6 and IRE1,and maintains them in inactive forms [30]. It is believed that up-regulation of GRP78 is pivotal for cell survival to facilitatefolding and assembly of ER proteins and prevent them fromaggregation during ER stress [30]. More importantly, their obser-vation that ADH transgene exaggerated alcohol intake inducedchanges in IRE1, eIF-2α, GRP78 and gadd153 suggests the directcontribution of acetaldehyde exposure to ER stress. Although Liand Ren [5] failed to dissect the interplay between insulinsensitivity and ER stress following alcohol intake, ER stress wasdocumented to trigger apoptosis in ischemia-reperfusion injury

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through suppression ofAkt. The preliminary evidence fromRen'sgroup indicated that ER stress might directly lead to cardiaccontractile dysfunction via an Akt-dependent pathway [31],consistent with the data of dampened Akt signaling observed intheir current study [5]. Taken together, these data suggest thatelevated cardiac acetaldehyde exposure via ADHmay exacerbatealcohol-induced cardiac dysfunction, hypertrophy, insulin insen-sitization and ER stress, indicating a key role of acetaldehyde inalcohol-induced cardiac dysfunction and insulin.

Oxidative stress at low levels is required for a variety ofcellular signaling, but at high levels has been attributed to cellpathology, including alcoholic cardiomyopathy although Li andRen did not emphasize this concept in the current study. In fact,several studies from Ren's lab have demonstrated the criticalcontribution of oxidative stress and damage caused by acute andchronic consumption of alcohol to alcoholic cardiomyopathy[4,17,32]. For instance, they have demonstrated that bothacetaldehyde and ethanol-induced overt ROS generation andapoptosis in human cardiac myocytes. Interestingly, acetalde-hyde-induced ROS generation and apoptosis was not onlyattenuated by ALDH2 transgene, but also by non-enzymaticantioxidants. Nishitani and Matsumoto demonstrated theexpression of GRP78 mRNA, as a marker of ER stress, anddecreased Akt activation in the cells exposed to alcohol. If cellswere treated with ADH inhibitors prior to alcohol exposure, Aktactivation and GRP78 mRNA expression were enhanced anddown-regulated, respectively, suggesting an intimate role ofacetaldehyde rather than alcohol itself in insulin insensitizationand ER stress [33], consistent with Li and Ren's observation [5].More interestingly, antioxidant may prevent alcohol-inducedinactivation of Akt and induction of ER stress, implicating theimportance of oxidative stress in the insensitization of insulinsignaling and induction of ER stresses elicited by ethanol.

The pivotal role of oxidative stress in alcoholic cardiomyo-pathy has been appreciated by several studies from Ren's lab[32,34–36]. Li and Ren have examined the effect of transgenicoverexpression of metallothionein (MT) on alcohol-inducedcardiac contractile dysfunction. Chronic intake of alcohol for12 weeks [34] or 16 weeks [35] caused overt cardiac dysfunctionalong with dampened whole body glucose tolerance, reducedexpression of total Akt, phosphorylated mTOR, and phosphory-lated p70s6k-to-p70s6k ratio as well as Akt kinase activity inalcohol consuming FVB mice. MT ablated reduced Akt proteinand kinase activity without affecting any other proteins or theirphosphorylation. These data suggest that chronic alcohol intakeinterrupted cardiac contractile function and Akt/mTOR/p70s6ksignaling [34,35]. In support of these observations, Wang et al.also demonstrated that chronic intake of alcohol caused a sig-nificantly severer cardiac fibrosis and oxidative damage in thehearts of MT-null mice than that in WT mice [37].

Since catalase (CAT) is responsible for detoxification ofhydrogen peroxide (H2O2) and may interfere with ethanol-induced cardiac toxicity, a cardiac-specific overexpression ofCAT transgenic mice were produced to overexpress CAT (~50-fold) in the heart, ranging from sarcoplasm, the nucleus andperoxisomeswithinmyocytes.Mechanical and intracellular Ca2+properties were evaluated in ventricular myocytes from CAT and

FVB mice. Transgenic CAT itself did not alter body andorgan weights, as well as myocyte contractile properties. Acuteexposure of ethanol elicited a concentration-dependent depres-sion in cell shortening and intracellular Ca2+ in FVB mice. Thealcohol-induced cardiac depression was significantly attenuatedin myocytes from CAT [32]. Most importantly Zhang et al. [36]have generated a ADH–CAT double transgenic mouse model bycrossing CAT and ADH lines. They provide evidence that ADHor ADH–CAT myocytes had higher acetaldehyde-producingability. Ethanol-induced depression on myocyte function wasaugmented in ADH group, but myocytes from CAT-ADH micedisplayed normal ethanol response. In addition, ADH amplifiedethanol-induced ROS generation, which was nullified by theCAT transgene. These data suggest that antioxidants CATandMTgene may effectively antagonize ADH-induced enhanced cardiacdepression in response to ethanol, via suppression of alcoholicoxidative stress as a pivotal mediator.

5. Summary

Since the concentrations of acetaldehyde usually achieved inthe body are in low micromolar range following moderateethanol intoxication, jury has been out as to whether and howacetaldehyde is the main mediator of ethanol-induced cytotoxiceffect. Recent advancement in ADH transgenic mice has made itpossible to artificially alter ethanol metabolism to evaluate therole of acetaldehyde in the progression of alcoholic cardiomyo-pathy. Based on the findings using ADH transgene, it may beconcluded that elevated acetaldehyde level during acute andchronic alcohol ingestion participate in the development ofalcoholic cardiomyopathy via alterations in excitation–contrac-tility coupling, cardiac function, insulin insensitization, ERstress, and oxidative stress, i.e. “acetaldehyde toxicity theory”.Since convincing human case study on heart function followingchronic alcohol intake is still lacking, further study is warrantedto elucidate if acetaldehyde is the ultimate cause of alcoholiccardiomyopathy.

Acknowledgments

Dr. Lu Cai is supported by the American Diabetes Associationand International Juvenile Diabetes Research Foundation.

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Lu CaiDepartment of Medicine,

the University of Louisville,KY 40202, USA

Department of Radiation Oncology,the University of Louisville,

KY 40202, USADepartment of Pharmacology and Toxicology,

the University of Louisville,KY 40202, USA

E-mail address: L0cai001@louisville.edu.Tel.: +1 502 852 5215; fax: +1 502 852 6904.

11 March 2008