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Acute Alcohol Modulates Cardiac Function as PI3K/Akt Regulates Oxidative Stress
Author(s) -
Umoh Nsini A.,
Walker Robin K.,
AlRubaiee Mustafa,
Jeffress Miara A.,
Haddad Georges E.
Publication year - 2014
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12459
Subject(s) - protein kinase b , oxidative stress , pi3k/akt/mtor pathway , ly294002 , medicine , endocrinology , chemistry , pharmacology , signal transduction , biochemistry
Background Clinical manifestations of alcohol abuse on the cardiac muscle include defective contractility with the development of heart failure. Interestingly, low alcohol consumption has been associated with reduced risk of cardiovascular disease. Although several hypotheses have been postulated for alcoholic cardiomyopathy and for the low‐dose beneficial cardiovascular effects, the precise mechanisms and mediators remain largely undefined. We hypothesize that modulation of oxidative stress by PI 3K/Akt plays a key role in the cardiac functional outcome to acute alcohol exposure. Methods Thus, acutely exposed rat cardiac tissue and cardiocytes to low ( LA : 5 mM), moderate ( MA : 25 mM), and high ( HA : 100 mM) alcohol were assessed for markers of oxidative stress in the presence and absence of PI 3K/Akt activators ( IGF ‐1 0.1 μ M or constitutively active PI 3K: Ad. BD 110 transfection) or inhibitor ( LY 294002 1 μ M or Akt‐negative construct Ad.Akt(K179M) transfection). Results Acute LA reduced Akt, superoxide dismutase ( SOD ‐3) and NF κB, ERK 1, and p38 MAPK gene expression. Acute HA only increased that of SOD ‐3 and NF κB. These effects were generally inhibited by Ad.Akt(K179M) and enhanced with Ad. BD 110 transfection. In parallel, LA reduced but HA enhanced Akt activity, which was reversed by IGF ‐1 and inhibited by Ad.Akt(K179M), respectively. Also, LA reduced caspase 3/7 activity and oxidative stress, while HA increased both. The former was blocked, while the latter effect was enhanced by Ad.Akt(K179M). The reverse was true with PI 3K/Akt activation. This translated into reduced viability with HA , with no effect with LA . On the functional level, acute LA improved cardiac output and ejection fraction, mainly through increased stroke volume. This was accompanied with enhanced end‐systolic pressure–volume relationship and preload recruitable stroke work. Opposite effect was recorded for HA . LA and HA in vivo functional effects were alleviated by LY and enhanced by IGF ‐1 treatment. Conclusions Acute LA and HA seem to oppositely affect cardiac function through modulation of oxidative stress where PI 3K/Akt plays a pivotal role.