Alcohol in Moderation, Cardioprotection, and Neuroprotection: Epidemiological Considerations and Mechanistic Studies

“In patients with cardiovascular risk factors such as hypercholesterolemia, hypertension, or aging (Zeiher et al., 1993), endothelial dysfunction predisposes to the development of structural vascular changes (Ross, 1993) and may play a critical role in acute MI and sudden death.”

“…that cardiovascular disease and stroke are 2 of the top 3 leading causes of mortality in developed countries and, according to a Lancet review (Ferri et al., 2005), new cases of dementia are being diagnosed about every 7 seconds worldwide, it seems imperative that as much as possible is…”

“These include dose-dependent associations of alcohol with lower risk of CHD but higher risk of hemorrhagic stroke throughout a recommended range of drinking, an increased risk of ischemic stroke with heavier drinking, and an emerging but somewhat variable association with lower risk of dementia.”

“Heavy alcohol consumption has long been associated with vascular as well as myocardial complications (Klatsky, 1996), whereas, as discussed earlier in this summary, several epidemiological studies suggest an inverse association between longterm moderate alcohol consumption and the risk of CHD and MI (Thun et al., 1997…”

“Ischemic or hyperthermic PC and brain neuroprotection, first described only about 2 decades ago (Chopp et al., 1989; Kitagawa et al., 1990), has spawned studies with traditionally toxic agents at exposures that mildly stress and thus precondition the system under study (Best et al., 1996; Leak et…”

“Meta-analyses of alcohol and stroke support this fully (Reynolds et al., 2003), suggesting 20% lower risk of ischemic stroke among lessthan-daily drinkers in cohort studies, but increased risk with heavier drinking, and a dose-dependent increase in risk for hemorrhagic stroke.”

“…conclusions about the relationship of average alcohol consumption with risk, suggesting 25% lower risk throughout a range of intake from about ½ drink per day through 2 drinks per day, but potentially higher risk at or above 6 drinks per day (Cleophas, 1999; Corrao et al., 2000; Maclure, 1993).”

“In the CHS and HPFS, alcohol intake correlates well with HDL-C levels, with coefficients of 0.25 to 0.35.”

“Studies with more common PC modalities—in particular, ischemic tolerance—have elucidated the involvement of early cellular ‘‘sensors’’ that trigger subsequent ‘‘transducer’’ mechanisms such as kinases, cytokines, and transcription factors upstream of hsp effectors (Dirnagl et al., 2003).”

“The phenomenon of preconditioning tissues or cells to generate a cytoprotective state or ‘‘phenotype’’ has been appreciated for some time (Gidday, 2006).”

“In patients with cardiovascular risk factors such as hypercholesterolemia, hypertension, or aging (Zeiher et al., 1993), endothelial dysfunction predisposes to the development of structural vascular changes (Ross, 1993) and may play a critical role in acute MI and sudden death.”

“, 1996) and other brain cultures (Brenneman et al., 1988).”

“Another well-known effect of alcohol is to increase the generation of ROS, including superoxide and the hydroxyethyl radical (Das and Vasudevan, 2007).”

“However, data from other studies appear somewhat mixed (Dufouil et al., 2000; Larrieu et al., 2004; Luchsinger et al., 2004; Ruitenberg et al., 2002; Truelsen et al., 2002), and this remains an important area for future investigation.”

“In the CHS and HPFS, alcohol intake correlates well with HDL-C levels, with coefficients of 0.25 to 0.35.”

“Endothelial NOS (eNOS) is a key regulator of vascular homeostasis, including basal vascular tone (blood flow) and blood pressure (Patel et al., 1999; Radomski and Moncada, 1993).”

“Clinical trials of short-term alcohol intake are scarce but suggest that moderate drinking enhances insulin sensitivity (Davies et al., 2002) and decreases plasma levels of C-reactive protein and fibrinogen (Sierksma et al., 2002).”

“These data suggest that alcohol pretreatment promotes rapid recruitment of PKC during stress to heart mitochondria, where PKC has been shown by other groups to preserve organelle integrity (Baines et al., 2003).”

“…stable alcohol ingestion over years exerts ‘‘PC-like’’ effects on glia and neurons akin to that which have been observed, leading to consequent dampening of the endogenous neuroinflammatory processes associated with sometimes accelerated or ‘‘pathological’’ brain aging (Chung et al., 2006).”

“…conclusions about the relationship of average alcohol consumption with risk, suggesting 25% lower risk throughout a range of intake from about ½ drink per day through 2 drinks per day, but potentially higher risk at or above 6 drinks per day (Cleophas, 1999; Corrao et al., 2000; Maclure, 1993).”

“However, data from other studies appear somewhat mixed (Dufouil et al., 2000; Larrieu et al., 2004; Luchsinger et al., 2004; Ruitenberg et al., 2002; Truelsen et al., 2002), and this remains an important area for future investigation.”

“Moreover, PC-dependent protection by alcohol against ischemic insult of the heart is attested to in many studies, as related earlier in this review (Agarwal, 2002; Sato et al., 2004), and the process is considered a likely component of cardioprotection in moderate alcohol drinkers (Miyamae et al.”

“In addition, alcohol consumption at low to moderate levels is associated with reduced C-reactive protein levels, a plasma marker of inflammation, and decreased production of inflammatory cytokines such as interleukin-6 (Albert et al., 2003; Das and Ursini, 2002; Korthuis, 2004, 2006).”

“…that light-moderate, nonbinge alcohol intake reduces the risk of CHD and, in agreement with an NIAAA position paper on moderate alcohol consumption (Gunzerath et al., 2004), that it does no apparent harm to cognition during aging, even possibly reducing the risk of cognitive decline ⁄dementia.”

“, 1997), decreasing platelet aggregation (Renaud and Ruf, 1996), enhancing fibrinolytic activity, decreasing fibrinogen (Aikens et al., 1998; Ridker et al., 1994) and decreasing I ⁄R injury (Miyamae et al.”

“In the CHS and HPFS, alcohol intake correlates well with HDL-C levels, with coefficients of 0.25 to 0.35.”

“This association has been observed for over 3 decades (Klatsky et al., 1974) and in populations worldwide consuming a variety of alcoholic beverages (Brenner et al.”

“However, data from other studies appear somewhat mixed (Dufouil et al., 2000; Larrieu et al., 2004; Luchsinger et al., 2004; Ruitenberg et al., 2002; Truelsen et al., 2002), and this remains an important area for future investigation.”

“Ischemic or hyperthermic PC and brain neuroprotection, first described only about 2 decades ago (Chopp et al., 1989; Kitagawa et al., 1990), has spawned studies with traditionally toxic agents at exposures that mildly stress and thus precondition the system under study (Best et al., 1996; Leak et…”

“The effect of alcohol on HDL-C alone appears to explain 50 to 70% of the observed inverse association of alcohol with risk of CHD (Mukamal et al., 2005c; Rimm et al., 1999).”

“Although part of the wine-mediated cardioprotection may be attributed to the alcohol (wines typically contain 10 to 12% alcohol), cardioprotective properties of red wine can be correlated with the presence of polyphenolic antioxidants, especially resveratrol, which is concentrated in red wine (Das and Maulik, 2006), b…”

“Importantly, this association was attributed to physiologically relevant trends in HDL cholesterol, fibrinogen, and hemoglobin A1C.”

“Clinical trials of short-term alcohol intake are scarce but suggest that moderate drinking enhances insulin sensitivity (Davies et al., 2002) and decreases plasma levels of C-reactive protein and fibrinogen (Sierksma et al., 2002).”

“Endothelial NOS (eNOS) is a key regulator of vascular homeostasis, including basal vascular tone (blood flow) and blood pressure (Patel et al., 1999; Radomski and Moncada, 1993).”

“Cardiac myocytes also constitutively express eNOS, which contributes to the regulation of myocardial contractility, heart rate (Kojda and Kottenberg, 1999), and cardiac oxygen consumption (Loke et al.”

“This U-shape exactly parallels findings on alcohol intake and MRI-identified cerebral white matter lesions (Mukamal et al., 2001), which are strong predictors of dementia in CHS (Kuller et al., 2003).”

“…effects of moderate alcohol and ⁄or polyphenols in increasing HDL (Gaziano et al., 1999; McConnell et al., 1997), decreasing platelet aggregation (Renaud and Ruf, 1996), enhancing fibrinolytic activity, decreasing fibrinogen (Aikens et al., 1998; Ridker et al., 1994) and decreasing I ⁄R injury…”

“Because alcohol enhances both basal and flow-stimulated NOS activity and NO production in vivo and in cultured endothelial cells, it has been suggested that production of this gaseous monoxide during the period of alcohol exposure may also serve as an important triggering element for the late phase of alcohol PC (Wall…”

“, 1974) and in populations worldwide consuming a variety of alcoholic beverages (Brenner et al., 2001; Yuan et al., 1997).”

“Upregulation of eNOS has been postulated to play a protective role in both congestive heart failure (Khadour et al., 1998) and myocardial I ⁄R (Kanno et al., 2000; Sumeray et al., 2000).”

“This isoenzyme is recognized as a powerful cytoprotectant in myocytes, through interactions with substrates and anchoring molecules in numerous compartments (Ping et al., 2001).”

“The effect of alcohol on HDL-C alone appears to explain 50 to 70% of the observed inverse association of alcohol with risk of CHD (Mukamal et al., 2005c; Rimm et al., 1999).”

“Cardiac myocytes also constitutively express eNOS, which contributes to the regulation of myocardial contractility, heart rate (Kojda and Kottenberg, 1999), and cardiac oxygen consumption (Loke et al., 1999).”

“Although the antioxidant properties of red wine constituents were originally thought to largely explain its cardioprotective effects, subsequent epidemiologic evidence has indicated that consumption of white wine, beer, or spirits is also beneficial (Das and Ursini, 2002; Korthuis, 2004; Shigematsu et al., 2003).”

“These include dose-dependent associations of alcohol with lower risk of CHD but higher risk of hemorrhagic stroke throughout a recommended range of drinking, an increased risk of ischemic stroke with heavier drinking, and an emerging but somewhat variable association with lower risk of dementia.”

“Accordingly, microassays to measure the activity of NADH-ubiquinone (Q1) reductase, or Complex I, in submitochondrial particles prepared from individual mouse hearts have been developed (Zhou et al., 2004).”

“In the CHS and HPFS, alcohol intake correlates well with HDL-C levels, with coefficients of 0.25 to 0.35.”

“, 2007), not to mention the brain with regard to stroke (Tsai et al., 2007).”

“Also, acute (Chen et al., 1999) and chronic (Zhou et al., 2002) cardioprotection stimulated by physiological concentrations of alcohol was associated with the selective activation of protein kinase Cepsilon (PKC ).”

“This cardioprotection has been attributed to the direct effects of moderate alcohol and ⁄or polyphenols in increasing HDL (Gaziano et al., 1999; McConnell et al., 1997), decreasing platelet aggregation (Renaud and Ruf, 1996), enhancing fibrinolytic activity, decreasing fibrinogen (Aikens et al.”

“…conclusions about the relationship of average alcohol consumption with risk, suggesting 25% lower risk throughout a range of intake from about ½ drink per day through 2 drinks per day, but potentially higher risk at or above 6 drinks per day (Cleophas, 1999; Corrao et al., 2000; Maclure, 1993).”

“The effect of alcohol on HDL-C alone appears to explain 50 to 70% of the observed inverse association of alcohol with risk of CHD (Mukamal et al., 2005c; Rimm et al., 1999).”

“In brain cultures, nonneurotoxic alcohol co-exposure can block excitotoxic [N-methyl-d-aspartate (NMDA) receptormediated] neurodegeneration (Belmadani et al., 2003; Cebere and Liljequist, 2003; Chandler et al., 1993; Wegelius and Korpi, 1995), consistent with NMDA receptor antagonism by alcohol.”

“Other feeding studies, including the longest randomized trial conducted to date (Marfella et al., 2006), also support a benefit of alcohol intake on insulin sensitivity (Davies et al., 2002) and on inflammatory markers (Sierksma et al., 2002).”

“, 1999), and improved metabolic function (Kanai et al., 1997).”

“However, data from other studies appear somewhat mixed (Dufouil et al., 2000; Larrieu et al., 2004; Luchsinger et al., 2004; Ruitenberg et al., 2002; Truelsen et al., 2002), and this remains an important area for future investigation.”

“Whether resveratrol is the essential component that is responsible for much of the cardioprotective effects of wine or the alcohol that is present in wines and is responsible for cardioprotection remains under considerable debate, but there is no doubt that resveratrol may protect the heart in many ways (Das et al., 2…”

“Whether resveratrol is the essential component that is responsible for much of the cardioprotective effects of wine or the alcohol that is present in wines and is responsible for cardioprotection remains under considerable debate, but there is no doubt that resveratrol may protect the heart in many ways (Das et al., 2…”

“, 2003), and the mechanism was ascribed to ROS trapping by alcohol (Cohen et al., 1976).”

“Additionally, the epidemiological literature contains about 19 longitudinal cohort studies between 1997 and 2008 (Mehlig et al., 2008; Orgogozo et al., 1997) that compare relative risk factors for either cognitive decline or dementia—both Alzheimer’s and cerebrovascular—in older moderate alcohol…”

“, 1994) and decreasing I ⁄R injury (Miyamae et al., 1997).”

“, 1998) and myocardial ischemia-reperfusion (Kanno et al., 2000; Sumeray et al., 2000).”

“Pretreatment of isolated hearts with a specific PKC antagonist peptide (Gray et al., 2004) prior to I ⁄R blocked alcohol-induced cardioprotection.”

“Although part of the wine-mediated cardioprotection may be attributed to the alcohol (wines typically contain 10 to 12% alcohol), cardioprotective properties of red wine can be correlated with the presence of polyphenolic antioxidants, especially resveratrol, which is concentrated in red wine (Das and Maulik, 2006), b…”

“Heavy alcohol consumption has long been associated with vascular as well as myocardial complications (Klatsky, 1996), whereas, as discussed earlier in this summary, several epidemiological studies suggest an inverse association between longterm moderate alcohol consumption and the risk of CHD and MI (Thun et al.”

“These observations have been extended to stroke models where antecedent alcohol has been shown to reduce I ⁄R-induced delayed neuronal death, neuronal and dendritic degeneration, oxidative DNA damage, glial cell activation, and neutrophil infiltration (Wang et al., 2007).”

“Whether resveratrol is the essential component that is responsible for much of the cardioprotective effects of wine or the alcohol that is present in wines and is responsible for cardioprotection remains under considerable debate, but there is no doubt that resveratrol may protect the heart in many ways (Das et al., 2…”

“Also, acute (Chen et al., 1999) and chronic (Zhou et al., 2002) cardioprotection stimulated by physiological concentrations of alcohol was associated with the selective activation of protein kinase Cepsilon (PKC ).”

“, 1997) as well as a reduction in mortality (Doll, 1997).”

“4B) (Pinder and Sandler, 2004) that can act within the nervous system.”

“…neurons in brain cortices of adult male ‘‘alcohol-preferring’’ rats chronically consuming 15% alcohol ⁄water were found to be protected from apoptosis due to peripherally injected pro-inflammatory lipopolysaccharide (Singh et al., 2007); however, a mechanistic interpretation was not provided.”

“The diabetic rats fed an alcohol diet showed a 52% reduction in advanced glycation end product when compared with diabetic controls (Al-Abed et al., 1999).”

“Considerable research indicates that heat shock proteins (hsp) can be putative neuroprotective ‘‘effectors’’ induced by ischemic and other delayed PC approaches (Carmel et al., 2004; Gidday, 2006).”

“Consumption of 3 or more drinks in 1 day also appears to acutely trigger ischemic stroke (Hillbom et al., 1995).”

“At the same time, concern continues to be raised about whether the lower risk associated with alcohol intake is related to bias by inclusion of former drinkers with preexisting illness or confounding by lifestyle factors associated with moderate drinking (Freiberg and Samet, 2005).”

“NO also inhibits smooth muscle proliferation, platelet aggregation, and monocyte adhesion making it an anti-thrombogenic agent (Lamas et al., 1998).”

“, 1999), and also, alcohol-mediated cardioprotection was achieved through the upregulation of eNOS expression (Abou-Agag et al., 2005).”

“In that regard, significant induction of hsp70 (Belmadani et al., 2004) and hsp27 occurred in HEC slices after 6 days of moderate alcohol exposure—but not at 4 days—which correlates with the onset of significant neuroprotection.”

“, 1997), decreasing platelet aggregation (Renaud and Ruf, 1996), enhancing fibrinolytic activity, decreasing fibrinogen (Aikens et al., 1998; Ridker et al., 1994) and decreasing ischemia-reperfusion injury (Miyamae et al.”

“There are a number of actions of NO that would be predicted to be cardioprotective, including decreased cardiac contractility (Kitakaze et al., 1996; Lamas et al., 1998), decreased coronary resistance (Kitakaze et al.”

“…development of an antiinflammatory phenotype in postcapillary venules such that these vessels fail to express P-selectin or support leukocyte adhesion and emigration in postischemic tissues (Dayton et al., 2005; Gaskin et al., 2007; Kamada et al., 2004; Wang et al., 2007; Yamaguchi et al., 2007).”

“, 1974) and in populations worldwide consuming a variety of alcoholic beverages (Brenner et al., 2001; Yuan et al., 1997).”

“This cardioprotection has been attributed to the direct effects of moderate alcohol and ⁄or polyphenols in increasing HDL (Gaziano et al., 1999; McConnell et al., 1997), decreasing platelet aggregation (Renaud and Ruf, 1996), enhancing fibrinolytic activity, decreasing fibrinogen (Aikens et al.”

“First, administration of NOS antagonists just prior to, but not 1 hour after, alcohol administration on day 1 abolishes the anti-adhesive effects of late alcohol preconditioning on day 2 (Yamaguchi et al., 2002; Yamaguchi et al., 2003; Yamaguchi et al., 2007).”

“Of importance, moderate (15–30 mM) subchronic alcohol preconditioning of HEC slice and cerebellar cultures prevented gp120IIIB-induced neurodegeneration (Belmadani et al., 2001; Collins et al., 2000).”

“Several neurotoxic HIV-1 proteins have been studied, and notably, glycoprotein 120 (gp120), the most potent in the laboratory, which can cause neuronal degeneration and apoptosis at low picomolar (10−12 molar) concentrations in hippocampal slice cultures (Aggoun-Zouaoui et al., 1996) and other brain cultures (Brennema…”

“In such studies, moderate concentrations in rats produced sustained cardioprotection requiring activation of mitochondrial KATP channels (Zhu et al., 2000), consistent with experiments published by other laboratories using canine models (Pagel et al., 2002).”

“…brain neuroprotection, first described only about 2 decades ago (Chopp et al., 1989; Kitagawa et al., 1990), has spawned studies with traditionally toxic agents at exposures that mildly stress and thus precondition the system under study (Best et al., 1996; Leak et al., 2006; Nvue et al., 2004).”

“Upregulation of eNOS has been postulated to play a protective role in both congestive heart failure (Khadour et al., 1998) and myocardial I ⁄R (Kanno et al.”

“…brain neuroprotection, first described only about 2 decades ago (Chopp et al., 1989; Kitagawa et al., 1990), has spawned studies with traditionally toxic agents at exposures that mildly stress and thus precondition the system under study (Best et al., 1996; Leak et al., 2006; Nvue et al., 2004).”

“Parenthetically, there is evidence that subchronic alcohol, albeit at high concentrations, perturbs NMDAR subunit composition in similar brain cultures (Snell et al., 2001).”

“First, administration of NOS antagonists just prior to, but not 1 hours after, alcohol administration on day 1 abolishes the anti-adhesive effects of late alcohol PC on day 2 (Yamaguchi et al., 2002, 2003, 2007).”

“Third, tissues pretreated with NO donors in lieu of alcohol develop an anti-inflammatory phenotype 24 hours after administration (Yamaguchi et al., 2002, 2007).”

“In brain cultures, nonneurotoxic alcohol co-exposure can block excitotoxic [N-methyl-d-aspartate (NMDA) receptormediated] neurodegeneration (Belmadani et al., 2003; Cebere and Liljequist, 2003; Chandler et al., 1993; Wegelius and Korpi, 1995), consistent with NMDA receptor antagonism by alcohol.”

“Of importance, activation of FAK has been linked to cytoprotective elevations in hsp70 and hsp27 (2 hsps elevated by alcohol PC) in severely stressed myocytes (Wei et al., 2006).”

“Consistent with ischemic PC results (Uchiyama et al., 2003), PKC activity, moderately elevated 15% after 2 days of alcohol, was increased 40% after 6 days of exposure.”

“In brain cultures, nonneurotoxic alcohol co-exposure can block excitotoxic [N-methyl-d-aspartate (NMDA) receptormediated] neurodegeneration (Belmadani et al., 2003; Cebere and Liljequist, 2003; Chandler et al., 1993; Wegelius and Korpi, 1995), consistent with NMDA receptor antagonism by alcohol.”

“Of importance, moderate (15 to 30 mM) subchronic alcohol PC of HEC slice and cerebellar cultures prevented gp120IIIB-induced neurodegeneration (Belmadani et al., 2001; Collins et al., 2000).”

“In brain cultures, nonneurotoxic alcohol co-exposure can block excitotoxic [N-methyl-d-aspartate (NMDA) receptormediated] neurodegeneration (Belmadani et al., 2003; Cebere and Liljequist, 2003; Chandler et al., 1993; Wegelius and Korpi, 1995), consistent with NMDA receptor antagonism by alcohol.”

“In rat heart, direct alcohol feeding led to a reduction of apoptotic cardiomyocyte death by reducing apoptotic signaling cascades, JNK-1 and c-Jun, and activating hsp 70, heme oxygenase, and SOD (Sato et al., 2004).”

“In such studies, moderate concentrations in rats produced sustained cardioprotection requiring activation of mitochondrial KATP channels (Zhu et al., 2000), consistent with experiments published by other laboratories using canine models (Pagel et al., 2002).”

“7 lmoles over 4 hours) pre- (or post-) I ⁄R was neuroprotective (Liao et al., 2003), and the mechanism was ascribed to ROS trapping by alcohol (Cohen et al.”

“…in humans, but analyses of the Determinants of Myocardial Infarction Onset Study [which included nearly 4,000 patients with acute myocardial infarction (MI)] raise the possibility that alcohol consumed 6 to 12 hours prior to onset of ischemia could attenuate infarct size (Mukamal et al., 1999).”

“Epidemiological evidence strongly suggests that light-tomoderate alcohol drinking, usually defined as consumption of 1 to 2 drinks per day (less than 30 g ⁄d), is associated with a reduced risk of CHD including ischemic heart disease, cardiomyopathy, diabetes, and stroke (Zakhari, 1999).”

“In rabbit heart, alcohol was found to exert a preconditioning (PC)-like effect mediated through adenosine receptors, PKC, and mitochondrial KATP channels (Krenz et al., 2004).”

“This is an important issue because isoform-selective PKC translocation and activation appears to play a critical role as an obligatory downstream signaling element in late alcohol PC (Dayton et al., 2005).”

“, 1996), diminished myocardial oxygen consumption (Okubo et al., 1999), and improved metabolic function (Kanai et al.”

“In addition, alcohol consumption at low to moderate levels is associated with reduced C-reactive protein levels, a plasma marker of inflammation, and decreased production of inflammatory cytokines such as interleukin-6 (Albert et al., 2003; Das and Ursini, 2002; Korthuis, 2004, 2006).”

“The protocol produces blood alcohol concentrations of approximately 10 mg ⁄dl or 4 mM at the time of killing (and maximal nighttime concentrations in comparable alcohol consumption studies of approximately 13 mM or 67 mg ⁄dl remain in a moderate range) (Chen et al., 2003).”

“…brain neuroprotection, first described only about 2 decades ago (Chopp et al., 1989; Kitagawa et al., 1990), has spawned studies with traditionally toxic agents at exposures that mildly stress and thus precondition the system under study (Best et al., 1996; Leak et al., 2006; Nvue et al., 2004).”

“Other mechanisms for the cardioprotective effect of light to moderate consumption have been discussed [116,128] but, based on current knowledge, appear to play less prominent roles in explaining the beneficial effects of regular light to moderate drinking.”

“Epidemiological studies show trends that light to moderate drinkers have reduced risk of dementia and cognitive decline in comparison to non-drinkers (reviewed Collins et al. 2009).”