Acute rosiglitazone treatment is cardioprotective against ischemia-reperfusion injury by modulating AMPK, Akt, and JNK signaling in nondiabetic mice

2011 ◽  
Vol 301 (3) ◽  
pp. H895-H902 ◽  
Author(s):  
Alex Morrison ◽  
Xiaoyan Yan ◽  
Chao Tong ◽  
Ji Li
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Mouse Heart ◽  
Jnk Signaling ◽  
Ppar Γ ◽  
Increased Risk ◽  
Amp Activated Protein Kinase

Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor (PPAR)-γ agonist, has been demonstrated to possess cardioprotective properties during ischemia-reperfusion. However, this notion remains controversial as recent evidence has suggested an increased risk in cardiac events associated with long-term use of RGZ in patients with type 2 diabetes. In this study, we tested the hypothesis that acute RGZ treatment is beneficial during I/R by modulating cardioprotective signaling pathways in a nondiabetic mouse model. RGZ (1 μg/g) was injected intravenously via the tail vein 5 min before reperfusion. Myocardial infarction was significantly reduced in mice treated with RGZ compared with vehicle controls (8.7% ± 1.1% vs. 20.2% ± 2.5%, P < 0.05). Moreover, isolated hearts were subjected to 20 min of global, no-flow ischemia in an ex vivo heart perfusion system. Postischemic recovery was significantly improved with RGZ treatment administered at the onset of reperfusion compared with vehicle ( P < 0.001). Immunoblot analysis data revealed that the levels of both phospho-AMP-activated protein kinase (Thr172) and phospho-Akt (Ser473) were significantly upregulated when RGZ was administered 5 min before reperfusion compared with vehicle. On the other hand, inflammatory signaling [phospho-JNK (Thr183/Tyr185)] was significantly downregulated as a result of RGZ treatment compared with vehicle ( P < 0.05). Intriguingly, pretreatment with the selective PPAR-γ inhibitor GW-9662 (1 μg/g iv) 10 min before reperfusion significantly attenuated these beneficial effects of RGZ on the ischemic heart. Taken together, acute treatment with RGZ can reduce ischemic injury in a nondiabetic mouse heart via modulation of AMP-activated protein kinase, Akt, and JNK signaling pathways, which is dependent on PPAR-γ activation.

scholarly journals Role of the energy sensor AMP-activated protein kinase in renal physiology and disease

2010 ◽  
Vol 298 (5) ◽  
pp. F1067-F1077 ◽  
Author(s):  
Kenneth R. Hallows ◽  
Peter F. Mount ◽  
Núria M. Pastor-Soler ◽  
David A. Power
Keyword(s):  
Protein Kinase ◽  
Ion Transport ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Physiology ◽  
Renal Diseases ◽  
Renal Hypertrophy ◽  
Energy Sensor ◽  
Energy Consuming ◽  
Amp Activated Protein Kinase

The ultrasensitive energy sensor AMP-activated protein kinase (AMPK) orchestrates the regulation of energy-generating and energy-consuming pathways. AMPK is highly expressed in the kidney where it is reported to be involved in a variety of physiological and pathological processes including ion transport, podocyte function, and diabetic renal hypertrophy. Sodium transport is the major energy-consuming process in the kidney, and AMPK has been proposed to contribute to the coupling of ion transport with cellular energy metabolism. Specifically, AMPK has been identified as a regulator of several ion transporters of significance in renal physiology, including the cystic fibrosis transmembrane conductance regulator (CFTR), the epithelial sodium channel (ENaC), the Na+-K+-2Cl− cotransporter (NKCC), and the vacuolar H+-ATPase (V-ATPase). Identified regulators of AMPK in the kidney include dietary salt, diabetes, adiponectin, and ischemia. Activation of AMPK in response to adiponectin is described in podocytes, where it reduces albuminuria, and in tubular cells, where it reduces glycogen accumulation. Reduced AMPK activity in the diabetic kidney is associated with renal accumulation of triglyceride and glycogen and the pathogenesis of diabetic renal hypertrophy. Acute renal ischemia causes a rapid and powerful activation of AMPK, but the functional significance of this observation remains unclear. Despite the recent advances, there remain significant gaps in the present understanding of both the upstream regulating pathways and the downstream substrates for AMPK in the kidney. A more complete understanding of the AMPK pathway in the kidney offers potential for improved therapies for several renal diseases including diabetic nephropathy, polycystic kidney disease, and ischemia-reperfusion injury.

Involvement of AMP-activated protein kinase in the protective effectof melatonin against renal ischemia reperfusion injury

2016 ◽  
Vol 40 ◽  
pp. 837-844
Author(s):  
Kaouther HADJ AYED TKA ◽  
Asma MAHFOUDH BOUSSAID ◽  
Kaouther KESSABI ◽  
Rym KAMMOUN ◽  
Imed MESSAOUDI ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Renal Ischemia Reperfusion Injury ◽  
Amp Activated Protein Kinase

scholarly journals The continuing evolution of the Langendorff and ejecting murine heart: new advances in cardiac phenotyping

2012 ◽  
Vol 303 (2) ◽  
pp. H156-H167 ◽  
Author(s):  
Ronglih Liao ◽  
Bruno K. Podesser ◽  
Chee Chew Lim
Keyword(s):  
Vascular Reactivity ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Isolated Heart ◽  
Ischemia Reperfusion ◽  
In Vitro Assays ◽  
Mouse Heart ◽  
Heart Preparation ◽  
The Impact

The isolated retrograde-perfused Langendorff heart and the isolated ejecting heart have, over many decades, resulted in fundamental discoveries that form the underpinnings of our current understanding of the biology and physiology of the heart. These two experimental methodologies have proven invaluable in studying pharmacological effects on myocardial function, metabolism, and vascular reactivity and in the investigation of clinically relevant disease states such as ischemia-reperfusion injury, diabetes, obesity, and heart failure. With the advent of the genomics era, the isolated mouse heart preparation has gained prominence as an ex vivo research tool for investigators studying the impact of gene modification in the intact heart. This review summarizes the historical development of the isolated heart and provides a practical guide for the establishment of the Langendorff and ejecting heart preparations with a particular emphasis on the murine heart. In addition, current applications and novel methods of recording cardiovascular parameters in the isolated heart preparation will be discussed. With continued advances in methodological recordings, the isolated mouse heart preparation will remain physiologically relevant for the foreseeable future, serving as an integral bridge between in vitro assays and in vivo approaches.

scholarly journals Metformin-Enhanced Cardiac AMP-Activated Protein Kinase/Atrogin-1 Pathways Inhibit Charged Multivesicular Body Protein 2B Accumulation in Ischemia–Reperfusion Injury

2021 ◽  
Vol 8 ◽  
Author(s):  
Tian Li ◽  
Yue Yin ◽  
Nan Mu ◽  
Yishi Wang ◽  
Manling Liu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Multivesicular Body ◽  
Autophagic Flux ◽  
H9c2 Cells ◽  
Body Protein ◽  
Amp Activated Protein Kinase

Background: Cardiac autophagic flux is impaired during myocardial ischemia/reperfusion (MI/R). Impaired autophagic flux may exacerbate MI/R injury. Charged multivesicular body protein 2B (CHMP2B) is a subunit of the endosomal sorting complex required for transport (ESCRT-III) complex that is required for autophagy. However, the reverse role of CHMP2B accumulation in autophagy and MI/R injury has not been established. The objective of this article is to elucidate the roles of AMP-activated protein kinase (AMPK)/atrogin-1 pathways in inhibiting CHMP2B accumulation in ischemia–reperfusion injury.Methods: Male C57BL/6 mice (3–4 months) and H9c2 cardiomyocytes were used to evaluate MI/R and hypoxia/reoxygenation (H/R) injury in vivo and in vitro, respectively. MI/R was built by a left lateral thoracotomy and occluded the left anterior descending artery. H9c2 cells were firstly treated in 95% N2 and 5% CO2 for 15 h and reoxygenation for 1 h. Metformin (100 mg/kg/d) and CHMP2B (Ad-CHMP2B) transfected adenoviruses were administered to the mice. The H9c2 cells were treated with metformin (2.5 mM), MG-132 (10 μM), bafilomycin A1 (10 nM), and compound C (20 μM).Results: Autophagic flux was found to be inhibited in H/R-treated cardiomyocytes and MI/R mice, with elevated cardiac CHMP2B accumulation. Upregulated CHMP2B levels in the in vivo and in vitro experiments were shown to inhibit autophagic flux leading to the deterioration of H/R-cardiomyocytes and MI/R injury. This finding implies that CHMP2B accumulation increases the risk of myocardial ischemia. Metformin suppressed CHMP2B accumulation and ameliorated H/R-induced autophagic dysfunction by activating AMPK. Activated AMPK upregulated the messenger RNA expression and protein levels of atrogin-1, a muscle-specific ubiquitin ligase, in the myocardium. Atrogin-1 significantly enhanced the interaction between atrogin-1 and CHMP2B, therefore, promoting CHMP2B degradation in the MI/R myocardium. Finally, this study revealed that metformin-inhibited CHMP2B accumulation induced autophagic impairment and ischemic susceptibility in vivo through the AMPK-regulated CHMP2B degradation by atrogin-1.Conclusion: Impaired CHMP2B clearance in vitro and in vivo inhibits autophagic flux and weakens the myocardial ischemic tolerance. Metformin treatment degrades CHMP2B through the AMPK-atrogin-1-dependent pathway to maintain the homeostasis of autophagic flux. This is a novel mechanism that enriches the understanding of cardioprotection.

Abstract 238: Toll-Like Receptor 4-Deficiency Improves Ischemic Cardiomyocytes Contractile Dysfunction via Augmentation of AMPK Activation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Peng Zhao ◽  
Leilei He ◽  
Heng Ma ◽  
Jing Li ◽  
Jingying Wang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Reperfusion Injury ◽  
Signaling Pathways ◽  
P38 Mapk ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Contractile Dysfunction ◽  
Ampk Activation ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

Myocardial ischemia/reperfusion injury involves a robust inflammatory response especially activation of toll-like receptor 4 (TLR4), a proximal signaling receptor in innate immune responses to lipopolysaccharide of Gram-negative pathogens. TLR4 is expressed in the heart and vasculature, the deficiency of which was shown to protect the heart against ischemia/reperfusion injury. However, the molecular mechanisms behind TLR4 deficiency-induced cardioprotection against ischemic damage remain unclear. The AMP-activated protein kinase (AMPK), an intracellular energy gauge, plays an important role in limiting cardiac damage following by ischemia, thus we hypothesized that AMPK maybe a mediator of TLR4-deficiency cardioprotection against ischemic injury. To test this hypothesis, In vivo regional ischemia was induced by occlusion of the left anterior descending (LAD) coronary artery in wild type (WT) C3H/HeN and TLR4-deficient C3H/HeJ mice, which carry a natural mutation of TLR4. Immunoblotting analysis was performed to assess the activation of AMPK and TLR4 downstream signal, the mitogen-activated protein kinase (MAPK). The endoplasmic reticulum (ER) chaperons, Grp78/BiP and Gadd153/CHOP, and ER integral membrane protein IRE1α were also monitored. The results demonstrated that C3H/HeJ hearts had impaired ischemic MAPK and AMPK activation compared to WT C3H/HeN hearts, i.e. activation of p38 MAPK and JNK was blunted, while ERK and AMPK signaling pathways were augmented during ischemia in C3H/HeJ hearts. Intriguingly, ischemia-stimulated ER stress was higher in WT C3H/HeN hearts than that in C3H/HeJ as demonstrated by up-regulation of Grp78/BiP, Gadd153/CHOP and IRE1α. Caspase-3 activity and TUNEL staining results showed that WT C3H/HeN hearts have more damages than those of C3H/HeJ hearts. Moreover, isolated cardiomyocytes from C3H/HeJ hearts showed resistance to ischemia-induced contractile dysfunction compared to WT C3H/HeN hearts. These findings suggest that the cardioprotective effects against ischemic injury of TLR4-deficient hearts may mediated through augmentation of AMPK and ERK while alleviation of p38 MAPK and JNK inflammatory signaling pathways. This research has received full or partial funding support from the American Heart Association, AHA National Center.

Simulated microgravity increases myocardial susceptibility to ischemia–reperfusion injury via a deficiency of AMP-activated protein kinase

2017 ◽  
Vol 95 (1) ◽  
pp. 59-71 ◽  
Author(s):  
Yuan-Ming Lu ◽  
Bo Jiao ◽  
Jun Lee ◽  
Lin Zhang ◽  
Zhi-Bin Yu
Keyword(s):  
Protein Kinase ◽  
Infarct Size ◽  
Simulated Microgravity ◽  
Ischemia Reperfusion Injury ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Ampk Phosphorylation ◽  
Amp Activated Protein Kinase

Gravitation is an important factor in maintaining cardiac contractility. Our study investigated whether simulated microgravity increases myocardial susceptibility to ischemia–reperfusion (IR) injury. Using the Langendorff-perfused heart model with 300 beats/min pacing, 4-week tail suspension (SUS) and control (CON) male Sprague-Dawley rats (n = 10 rats/group) were subjected to 60 min of left anterior descending coronary artery (LAD) occlusion followed by 120 min of reperfusion. Left ventricular end-systolic pressure (LVESP), left ventricular end-diastolic pressure (LVEDP), creatine kinase (CK) and lactate dehydrogenase (LDH) activity, and infarct size were assessed. Data demonstrated that there were significantly increased LVEDP, CK, LDH, and infarct size in SUS compared with CON (P < 0.05), accompanied by decreased LVESP (P < 0.05). Furthermore, TUNEL-positive cardiomyocytes were higher in SUS than that in CON (P < 0.01), and AMP-activated protein kinase (AMPK) phosphorylation and Bcl-2/Bax in SUS were less compared with CON (P < 0.05). Similarly, isolated hearts pre-treated with A-769662 exhibited better recovery of cardiac function, increased AMPK phosphorylation, and reduced necrosis and apoptosis. Furthermore, AMPKα protein showed a significant suppression in 4-week hindlimb unweighting rats. These results suggest that AMPK deficiency increases myocardial susceptibility to IR injury in rats subjected to simulated microgravity.

Acute protection of ischemic heart by FGF-2: involvement of FGF-2 receptors and protein kinase C

2002 ◽  
Vol 282 (3) ◽  
pp. H1071-H1080 ◽  
Author(s):  
Zhi-Sheng Jiang ◽  
Raymond R. Padua ◽  
Haisong Ju ◽  
Bradley W. Doble ◽  
Yan Jin ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Ischemia Reperfusion Injury ◽  
Troponin T ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Kinase C ◽  
Developed Pressure ◽  
Improved Function

We examined the effect of fibroblast growth factor (FGF)-2 on myocardial resistance to injury when administered after the onset of ischemia , in vivo and ex vivo, and the role of FGF-2 receptors and protein kinase C (PKC). FGF-2 was injected into the left ventricle of rats undergoing permanent surgical coronary occlusion leading to myocardial infarction (MI). After 24 h, FGF-2-treated hearts displayed significantly reduced injury, determined by histological staining and troponin T release, and improved developed pressure compared with untreated controls. An FGF-2 mutant with diminished affinity for the tyrosine kinase FGF-2 receptor 1 (FGFR1) was not cardioprotective. FGF-2-treated hearts retained improved function and decreased damage at 6 wk after MI. In the ex vivo heart, FGF-2 administration during reperfusion after 30-min ischemia improved functional recovery and increased relative levels of PKC subtypes α, ε, and ζ in the particulate fraction, in a chelerythrine-preventable mode; it also decreased loss of energy metabolites. We conclude that intramyocardial FGF-2 administration shortly after the onset of ischemia confers protection from acute and chronic cardiac dysfunction and damage; FGF-2 delivered during reperfusion protects from ischemia-reperfusion injury; and protection by FGF-2 requires intact binding to FGFR1 and is likely mediated by PKC.

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