Multiple antiapoptotic targets of the PI3K/Akt survival pathway are activated by epoxyeicosatrienoic acids to protect cardiomyocytes from hypoxia/anoxia

Dhanasekaran, Anuradha; Gruenloh, Stephanie; Buonaccorsi, J. Noelle; Zhang, Rong; Gross, Garrett J.; Falck, John R.; Patel, Paresh K.; Jacobs, Elizabeth R.; Medhora, Meetha

doi:10.1152/ajpheart.00979.2007

Cited by 148 publications

(136 citation statements)

References 69 publications

(81 reference statements)

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“…We next studied caspase-3 activation since it has been implicated in gut injury models of T/HS (39,40), hypoxia (20), and ischemia (7,25) and the caspase-3 promoter contains a functional HIF-1 response element (65). A significant decrease in the cleavage of caspase-3 (Fig.…”

Section: Resultsmentioning

confidence: 99%

HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury

Feinman

Deitch

Watkins

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

125

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mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 299: G833-G843, 2010. First published August 5, 2010 doi:10.1152/ajpgi.00065.2010.-Acute lung injury (ALI) and the development of the multiple organ dysfunction syndrome (MODS) are major causes of death in trauma patients. Gut inflammation and loss of gut barrier function as a consequence of splanchnic ischemia-reperfusion (I/R) have been implicated as the initial triggering events that contribute to the development of the systemic inflammatory response, ALI, and MODS. Since hypoxia-inducible factor (HIF-1) is a key regulator of the physiological and pathophysiological response to hypoxia, we asked whether HIF-1 plays a proximal role in the induction of gut injury and subsequent lung injury. Utilizing partially HIF-1␣-deficient mice in a global trauma hemorrhagic shock (T/HS) model, we found that HIF-1 activation was necessary for the development of gut injury and that the prevention of gut injury was associated with an abrogation of lung injury. Specifically, in vivo studies demonstrated that partial HIF-1␣ deficiency ameliorated T/HS-induced increases in intestinal permeability, bacterial translocation, and caspase-3 activation. Lastly, partial HIF-1␣ deficiency reduced TNF-␣, IL-1␤, cyclooxygenase-2, and inducible nitric oxide synthase levels in the ileal mucosa after T/HS whereas IL-1␤ mRNA levels were reduced in the lung after T/HS. This study indicates that prolonged intestinal HIF-1 activation is a proximal regulator of I/R-induced gut mucosal injury and gut-induced lung injury. Consequently, these results provide unique information on the initiating events in trauma-hemorrhagic shock-induced ALI and MODS as well as potential therapeutic insights. hemorrhagic shock; inflammation; multiple organ dysfunction syndrome; acute lung injury IN PATIENTS SUSTAINING major trauma, the development of the systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction (MODS) is a major clinical problem resulting in 50 -80% of all deaths in surgical intensive care units. Since the pathophysiology of this syndrome remains incompletely understood and therapy remains largely supportive (16), studies focusing on the basic biology of traumainduced SIRS, organ injury/dysfunction, and MODS have been major areas of investigation. These mechanistic studies have generated several working hypotheses, one of which is the gut hypothesis of MODS. A key element in the gut hypothesis of MODS is that a splanchnic ischemia-reperfusion (I/R) insult leading to gut inflammation and loss of barrier function is the initial triggering event that turns the gut into the "motor" of MODS (19). However, the exact mechanisms by which gut I/R leads to intestinal injury and how an intestinal ischemic insult is transduced into a systemic inflammatory response remains incomplete. To date, the majority of the molecular and cellular studies investigating shock-induced gut injury and gut-induced MODS have focused pr...

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Section: Resultsmentioning

confidence: 99%

HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury

Feinman

Deitch

Watkins

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

125

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“…In addition to the brain, crosstalk between iNOS and HIF-1␣ has also been demonstrated in trauma hemorrhagic shock-induced hepatic injury (26). Furthermore, recent studies have demonstrated caspase-3 activation in models of hemorrhagic shock (28,29), hypoxia (13), and ischemia (2,18) and that increased caspase-3 protein and activity are regulated via iNOS (28,36). Thus, our results showing that HIF-1 activation is associated with both increased iNOS expression and caspase-3 activation in the ileal mucosa are consistent with this published work, as well as studies showing that a functional HIF-1 response element is present within the caspase-3 promoter (52).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury

Kannan

Colorado

Reino

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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DZ, Semenza GL, Deitch EA, Feinman R. Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury. Am J Physiol Gastrointest Liver Physiol 300: G853-G861, 2011. First published December 23, 2010 doi:10.1152/ajpgi.00459.2010.-Gut injury and loss of normal intestinal barrier function are key elements in the paradigm of gutorigin systemic inflammatory response syndrome, acute lung injury, and multiple organ dysfunction syndrome (MODS). As hypoxiainducible factor (HIF-1) is a critical determinant of the physiological and pathophysiological response to hypoxia and ischemia, we asked whether HIF-1 plays a proximal role in the induction of gut injury and subsequent lung injury. Using partially HIF-1␣-deficient mice in an isolated superior mesenteric artery occlusion (SMAO) intestinal ischemia reperfusion (I/R) injury model (45 min SMAO followed by 3 h of reperfusion), we showed a direct relationship between HIF-1 activation and intestinal I/R injury. Specifically, partial HIF-1␣ deficiency attenuated SMAO-induced increases in intestinal permeability, lipid peroxidation, mucosal caspase-3 activity, and IL-1␤ mRNA levels. Furthermore, partial HIF-1␣ deficiency prevented the induction of ileal mucosal inducible nitric oxide synthase (iNOS) protein levels after SMAO and iNOS deficiency ameliorated SMAO-induced villus injury. Resistance to SMAO-induced gut injury was also associated with resistance to lung injury, as reflected by decreased levels of myeloperoxidase, IL-6 and IL-10 in the lungs of HIF-1␣ ϩ/Ϫ mice. In contrast, a short duration of SMAO (15 min) followed by 3 h of reperfusion neither induced mucosal HIF-1␣ protein levels nor caused significant gut and lung injury in wild-type or HIF-1␣ ϩ/Ϫ mice. This study indicates that intestinal HIF-1 activation is a proximal regulator of I/R-induced gut mucosal injury and gut-induced lung injury. However, the duration and severity of the gut I/R insult dictate whether HIF-1 plays a gut-protective or deleterious role.inflammation; inducible nitric oxide synthase; mucosal injury MULTIPLE ORGAN DYSFUNCTION syndrome (MODS) is the major cause of morbidity and mortality in critically ill patients. A key paradigm in the development of the systemic inflammatory response syndrome (SIRS) and acute respiratory distress syndrome (ARDS) that culminates in multiple organ dysfunction syndrome (MODS) is loss of intestinal barrier function (10, 12). Intestinal ischemia reperfusion (I/R) injury occurs in different clinical settings, such as trauma, shock, burn, mesenteric artery occlusion, abdominal, cardiac bypass, and thoracic vascular surgery, as well as small intestinal transplantation.Because the gut acts as the "motor" of SIRS, ARDS, and MODS (6) and therapy for the critically ill patient remains largely supportive, studies identifying the underlying pathophysiological factors in the gut that initiate and propagate SIRS, ARDS, and MODS are of critical importance. To date, studies investigating the gut inflammatory/injurious response have primarily fo...

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“…Cardiovascular death, a nonfatal ACS event, anti-infl ammation by attenuating nuclear factor B signaling ( 24 ), and antiapoptosis by promoting phosphoinositide-3-kinase/Akt signaling ( 25 ). Consequently, promoting the effects of EETs, most notably by inhibiting sEH and increasing endogenous EET levels, has emerged as a cardiovascular protective therapeutic strategy with potential clinical utility ( 26 ).…”

Section: Risk Of Future Cardiovascular Eventsmentioning

confidence: 99%

Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study

Oni‐Orisan

Edin

Lee

et al. 2016

Journal of Lipid Research

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Multiple antiapoptotic targets of the PI3K/Akt survival pathway are activated by epoxyeicosatrienoic acids to protect cardiomyocytes from hypoxia/anoxia

Abstract: Dhanasekaran A, Gruenloh SK, Buonaccorsi JN, Zhang R, Gross GJ, Falck JR, Patel PK, Jacobs ER, Medhora M. Multiple antiapoptotic targets of the PI3K/Akt survival pathway are activated by epoxyeicosatrienoic acids to protect cardiomyocytes from hypoxia/anoxia.

Cited by 148 publications

References 69 publications

HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury

HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury

Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury

Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study

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