Background-Chronic alcoholism leads to the onset and progression of alcoholic cardiomyopathy through toxic mechanisms of ethanol and its metabolite, acetaldehyde. This study examined the impact of altered acetaldehyde metabolism through systemic transgenic overexpression of aldehyde dehydrogenase-2 (ALDH2) on chronic alcohol ingestion-induced myocardial damage. Methods and Results-ALDH2 transgenic mice were produced with the chicken ␤-actin promoter. Wild-type FVB and ALDH2 mice were placed on a 4% alcohol diet or a control diet for 14 weeks. Myocardial and cardiomyocyte contraction, intracellular Ca 2ϩ handling, histology (hematoxylin and eosin, Masson trichrome), protein damage, and apoptosis were determined. Western blot was used to monitor the expression of NADPH oxidase, calcineurin, apoptosisstimulated kinase (ASK-1), glycogen synthase kinase-3␤ (GSK-3␤), GATA4, and cAMP-response element binding (CREB) protein. ALDH2 reduced the chronic alcohol ingestion-induced elevation in plasma and tissue acetaldehyde levels. Chronic alcohol consumption led to cardiac hypertrophy, reduced fractional shortening, cell shortening, and impaired intracellular Ca

Background-Elderly patients are more sensitive than younger patients to myocardial ischemia, which results in higher mortality. We investigated how aging affects the cardioprotective AMP-activated protein kinase (AMPK) signaling pathway. Methods and Results-Ischemic AMPK activation was impaired in aged compared with young murine hearts. The expression and secretion of the AMPK upstream regulator, macrophage migration inhibitory factor (MIF), were lower in aged compared with young adult hearts. Additionally, the levels of hypoxia-inducible factor 1␣, a known transcriptional activator of MIF, were reduced in aged compared with young hearts. Ischemia-induced AMPK activation in MIF knockout mice was blunted, leading to greater contractile dysfunction in MIF-deficient than in wild-type hearts. Furthermore, intramyocardial injection of adenovirus encoding MIF in aged mice increased MIF expression and ischemic AMPK activation and reduced infarct size. Conclusions-An impaired MIF-AMPK activation response in senescence thus may be attributed to an agingassociated defect in hypoxia-inducible factor 1␣, the transcription factor for MIF. In the clinical setting, impaired cardiac hypoxia-inducible factor 1␣ activation and consequent reduced MIF expression may play an important role in the increased susceptibility to myocardial ischemia observed in older cardiac patients. (Circulation. 2010;122: 282-292.)

The purpose of this study was to evaluate the effect of endurance exercise training on both locomotor skeletal muscle collagen characteristics and passive stiffness properties in the young adult and old rat. Young (3-mo-old) and senescent (23-mo-old) male Fischer 344 rats were randomly assigned to either a control or exercise training group [young control (YC), old control (OC), young trained (YT), old trained (OT)]. Exercise training consisted of treadmill running at approximately 70% of maximal oxygen consumption (45 min/day, 5 days/wk, for 10 wk). Passive stiffness (stress/strain) of the soleus (Sol) muscle from all four groups was subsequently measured in vitro at 26 degreesC. Stiffness was significantly greater for Sol muscles in OC rats compared with YC rats, but in OT rats exercise training resulted in muscles with stiffness characteristics not different from those in YC rats. Sol muscle collagen concentration and the level of the nonreducible collagen cross-link hydroxylysylpyridinoline (HP) significantly increased from young adulthood to senescence. Although training had no effect on Sol muscle collagen concentration in either age group, it resulted in a significant reduction in the level of Sol muscle HP in OT rats. In contrast, exercise had no effect on HP in the YT animals. These findings indicate that 10 wk of endurance exercise significantly alter the passive viscoelastic properties of Sol muscle in old but not in young adult rats. The coincidental reduction in the principal collagen cross-link HP also observed in response to training in OT muscle highlights the potential role of collagen in influencing passive muscle viscoelastic properties.

A "longevity " gene, sirtuin 1 (SIRT1), can attenuate age-dependent induction of left ventricular dysfunction. This study aimed to characterize the role of SIRT1 in the tolerance of aged heart to ischemic insults. Male C57BL/6 young (4-6 mo) and aged (24-26 mo) mice were used to determine the role of SIRT1 in myocardial ischemia/reperfusion (I/R) tolerance. SIRT1 localization was assessed by confocal microscopy. Immunoblotting was used to evaluate SIRT1 expression and translocation. The results demonstrated that SIRT1 is expressed predominantly as a sumoylated form in cardiomyocyte nuclei. Moreover, cardiac overexpression of desumoylase, sentrin-specific protease 2 (SENP2), significantly reduces nuclear sumoylated SIRT1 levels (P<0.05). Interestingly, I/R stress leads to desumoylation and translocation of nuclear SIRT1 into the cytoplasm in aged but not in young hearts. SIRT1 activity in ischemic young hearts was 3.2-fold higher than that seen in ischemic aged hearts, which suggests that aging causes impaired nucleocytoplasmic shuttling and activation of SIRT1 during ischemic stress. The infarct size in aged and Sirt1(+/-) knockout hearts was higher than that observed in young and Sirt1(+/+) WT littermate hearts, respectively (all P<0.05). SIRT1 agonist, SRT1720, reduced myocardial infarction in both aged and Sirt1(+/-) hearts. Therefore, impaired cardiac SIRT1 activity plays a critical role in the observed increase in susceptibility of the aged heart to I/R injury. SIRT1 agonist can restore this aging-related loss of cardioprotection.