Liver apoptosis is age dependent and is reduced by activation of peroxisome proliferator-activated receptor-γ in hemorrhagic shock

Zingarelli, Basilia; Chima, Ranjit S.; O’Connor, Michael; Piraino, Giovanna; Denenberg, Alvin; Hake, Paul W.

doi:10.1152/ajpgi.00262.2009

Cited by 10 publications

(7 citation statements)

References 38 publications

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“…We have previously demonstrated that PPARγ plays an important protective role in hemorrhagic shock, since PPARγ ligands are able to reduce organ injury and improve cardiovascular function in male rodents [42–44]. In the present study, we found that PPARγ activity was upregulated in an age-dependent, but not gender-dependent manner after hemorrhagic shock.…”

Section: Discussionsupporting

confidence: 63%

Metformin ameliorates gender-and age-dependent hemodynamic instability and myocardial injury in murine hemorrhagic shock

Matsiukevich¹,

Piraino²,

Lahni³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Severity of multiple organ failure is significantly impacted by age and gender in patients with hemorrhagic shock. However, the molecular mechanisms underlying the enhanced organ injury are not fully understood. AMP-activated protein kinase (AMPK) is a pivotal orchestrator of metabolic responses during stress. We investigated whether hemorrhage-induced myocardial injury is age and gender dependent and whether treatment with metformin, an AMPK activator, affords cardioprotective effects. C57/BL6 young (3–5 months) and mature (9–12 months) male and female mice were subjected to hemorrhagic shock by blood withdrawing followed by resuscitation with blood and Lactated Ringer’s solution. Vehicle-treated young and mature mice of both genders had a similar elevation of plasma inflammatory cytokines at 3 hours after resuscitation. However, vehicle-treated male mature mice experienced hemodynamic instability and higher myocardial damage than young male mice, as evaluated by echocardiography, histology and cardiovascular injury biomarkers. There was also a gender-dependent difference in cardiovascular injury in the mature group as vehicle-treated male mice exhibited more severe organ injury than female mice. At molecular analysis, vehicle-treated mature mice of both genders exhibited a marked downregulation of AMPKα activation and nuclear translocation of peroxisome proliferator-activated receptor γ co-activator α when compared with young mice. Treatment with metformin improved cardiovascular function and survival in mature animals of both genders. However, specific cardioprotective effects of metformin were gender-dependent. Metformin did not affect hemodynamic or inflammatory responses in young animals. Thus, our data suggest that targeting metabolic recovery with metformin may be a potential treatment approach in severe hemorrhage in adult population.

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Section: Discussionsupporting

confidence: 63%

Metformin ameliorates gender-and age-dependent hemodynamic instability and myocardial injury in murine hemorrhagic shock

Matsiukevich¹,

Piraino²,

Lahni³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…A non-significant trend towards higher mitochondrial pro- to anti-apoptotic ratio (BAX: Bcl-2) in old age was also observed however we did not find increased cytochrome C, AIF release or caspase-9 activation, which are intermediates involved in signaling downstream apoptosis. Consistent with other research (Molpeceres et al, 2007; Zhang et al, 2002; Zingarelli et al, 2010) we found increased protein levels of apoptosis markers activated caspase-3, -6 and -7 in old age and a trend towards an increase in apoptotic DNA fragmentation that may be activated by mechanisms of apoptosis (Elmore, 2007) other than the intrinsic death pathway. These results suggest that in old Fischer 344 rats complex changes occur in the intrinsic cell death pathway and apoptosis that include altered mitochondrial apoptotic protein levels, subcellular localization, signaling and increased overall apoptosis.…”

Section: Discussionsupporting

confidence: 92%

The effect of aging on mitochondrial and cytosolic hepatic intrinsic death pathway and apoptosis associated proteins in Fischer 344 rats

Mach

Huizer-Pajkos

Kane

et al. 2015

Experimental Gerontology

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Apoptosis is increased in the liver in old age and is a common pathological feature of liver disease. The mitochondria play a key role in regulating apoptosis via the intrinsic death pathway. As the effect of aging on this pathway is unclear, we aimed to characterize the impact of aging on the hepatic intrinsic death pathway and apoptosis. Livers from young adult (6.6 ± 0.3 months, n = 9) and old (25.4 ± 0.7 months, n = 9) male Fischer 344 rats were extracted for cellular fractionation and immunobloting. In old age there were lower mitochondrial protein levels of pro-apoptotic BAK, BID, tBID and VDAC1 (p < 0.05) and of anti-apoptotic Bcl-2. Compared to young, old rats had lower cytosolic protein levels of pro-apoptotic BAX, BAK, BID, tBID and anti-apoptotic Bcl-xL (p < 0.05). BAK, Bcl-2 and Bcl-xL were found in the cytosol. Furthermore with old age, cytosolic protein levels of cytochrome C, AIF and cleaved caspase-9 did not change but activation of caspase-3, -6 and -7 increased (p < 0.05) and DNA fragmentation trended to increase. Our results suggest an age-related decline in the levels of a number of proteins involved in the intrinsic death pathway, an uncoupling of intermediate apoptosis signaling and increased cellular apoptosis in the liver in old age.

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“…Pgc-1α acts with transcription factors such as Ppar-γ, retinoid receptor (RXR)-α and nuclear respiratory factor-1 (Nrf-1). It has been shown previously that Ppar expression after T-H decreases, and its augmented expression reduces liver apoptosis following T-H (46). Upon events such as oxidative or cold stress, expression of Pgc-1α is upregulated by transcriptional activities and downstream target genes are activated (47).…”

Section: Discussionmentioning

confidence: 95%

Aging Influences Cardiac Mitochondrial Gene Expression and Cardiovascular Function following Hemorrhage Injury

Jian

Yang

Chen

et al. 2010

Mol Med

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Cardiac dysfunction and mortality associated with trauma and sepsis increase with age. Mitochondria play a critical role in the energy demand of cardiac muscles, and thereby on the function of the heart. Specific molecular pathways responsible for mitochondrial functional alterations after injury in relation to aging are largely unknown. To further investigate this, 6-and 22-monthold rats were subjected to trauma-hemorrhage (T-H) or sham operation and euthanized following resuscitation. Left ventricular tissue was profiled using our custom rodent mitochondrial gene chip (RoMitochip). Our experiments demonstrated a declined left ventricular performance and decreased alteration in mitochondrial gene expression with age following T-H and we have identified c-Myc, a pleotropic transcription factor, to be the most upregulated gene in 6-and 22-month-old rats after T-H. Following T-H, while 142 probe sets were altered significantly (39 up and 103 down) in 6-month-old rats, only 66 were altered (30 up and 36 down) in 22-month-old rats; 36 probe sets (11 up and 25 down) showed the same trend in both groups. The expression of c-Myc and cardiac death promoting gene Bnip3 were increased, and Pgc1-α and Ppar-α a decreased following T-H. Eleven tRNA transcripts on mtDNA were upregulated following T-H in the aged animals, compared with the sham group. Our observations suggest a cmyc-regulated mitochondrial dysfunction following T-H injury and marked decrease in age-dependent changes in the transcriptional profile of mitochondrial genes following T-H, possibly indicating cellular senescence. To our knowledge, this is the first report on mitochondrial gene expression profile following T-H in relation to aging.

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Liver apoptosis is age dependent and is reduced by activation of peroxisome proliferator-activated receptor-γ in hemorrhagic shock

Abstract: Zingarelli B, Chima R, O'Connor M, Piraino G, Denenberg A, Hake PW. Liver apoptosis is age dependent and is reduced by activation of peroxisome proliferator-activated receptor-␥ in hemorrhagic shock.

Cited by 10 publications

References 38 publications

Metformin ameliorates gender-and age-dependent hemodynamic instability and myocardial injury in murine hemorrhagic shock

Metformin ameliorates gender-and age-dependent hemodynamic instability and myocardial injury in murine hemorrhagic shock

The effect of aging on mitochondrial and cytosolic hepatic intrinsic death pathway and apoptosis associated proteins in Fischer 344 rats

Aging Influences Cardiac Mitochondrial Gene Expression and Cardiovascular Function following Hemorrhage Injury

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