scholarly journals Dietary α-Linolenic Acid Counters Cardioprotective Dysfunction in Diabetic Mice: Unconventional PUFA Protection

Nutrients ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2679 ◽  
Author(s):  
Jake S. Russell ◽  
Tia A. Griffith ◽  
Saba Naghipour ◽  
Jelena Vider ◽  
Eugene F. Du Toit ◽  
...  
Keyword(s):  
Linolenic Acid ◽  
Mitochondrial Function ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Omega 3 ◽  
Carbohydrate Feeding ◽  
Cardiometabolic Disorders ◽  
Stress Kinase ◽  
Perfused Hearts

Whether dietary omega-3 (n-3) polyunsaturated fatty acid (PUFA) confers cardiac benefit in cardiometabolic disorders is unclear. We test whether dietary α-linolenic acid (ALA) enhances myocardial resistance to ischemia-reperfusion (I-R) and responses to ischemic preconditioning (IPC) in type 2 diabetes (T2D); and involvement of conventional PUFA-dependent mechanisms (caveolins/cavins, kinase signaling, mitochondrial function, and inflammation). Eight-week male C57Bl/6 mice received streptozotocin (75 mg/kg) and 21 weeks high-fat/high-carbohydrate feeding. Half received ALA over six weeks. Responses to I-R/IPC were assessed in perfused hearts. Localization and expression of caveolins/cavins, protein kinase B (AKT), and glycogen synthase kinase-3β (GSK3β); mitochondrial function; and inflammatory mediators were assessed. ALA reduced circulating leptin, without affecting body weight, glycemic dysfunction, or cholesterol. While I-R tolerance was unaltered, paradoxical injury with IPC was reversed to cardioprotection with ALA. However, post-ischemic apoptosis (nucleosome content) appeared unchanged. Benefit was not associated with shifts in localization or expression of caveolins/cavins, p-AKT, p-GSK3β, or mitochondrial function. Despite mixed inflammatory mediator changes, tumor necrosis factor-a (TNF-a) was markedly reduced. Data collectively reveal a novel impact of ALA on cardioprotective dysfunction in T2D mice, unrelated to caveolins/cavins, mitochondrial, or stress kinase modulation. Although evidence suggests inflammatory involvement, the basis of this “un-conventional” protection remains to be identified.

scholarly journals Tanshinone IIA combined with CsA inhibit myocardial cell apoptosis induced by renal ischemia-reperfusion injury in obese rats

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
He Tai ◽  
Xiao-lin Jiang ◽  
Zhi-ming Lan ◽  
Yue Li ◽  
Liang Kong ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Cell Apoptosis ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Abdominal Cavity ◽  
Myocardial Cell ◽  
Renal Ischemia ◽  
Tanshinone Iia ◽  
Obese Rats

Abstract Background Acute myocardial injury (AMI), which is induced by renal ischemia-reperfusion (IR), is a significant cause of acute kidney injury (AKI)-related associated death. Obesity increases the severity and frequency of AMI and AKI. Tanshinone IIA (TIIA) combined with cyclosporine A (CsA) pretreatment was used to alleviate myocardial cell apoptosis induced by renal IR, and to determine whether TIIA combined with CsA would attenuate myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats. Methods Male rates were fed a high fat diet for 8 weeks to generate obesity. AKI was induced by 30 min of kidney ischemia followed 24 h of reperfusion. Obese rats were given TIIA (10 mg/kg·d) for 2 weeks and CsA (5 mg/kg) 30 min before renal IR. After 24 h of reperfusion, the rats were anaesthetized, the blood were fetched from the abdominal aorta and kidney were fetched from abdominal cavity, then related indicators were examined. Results TIIA combined with CsA can alleviate the pathohistological injury and apoptosis induced by renal IR in myocardial cells. TIIA combined with CsA improved cardiac function after renal ischemia (30 min)-reperfusion (24 h) in obese rats. At the same time, TIIA combined with CsA improved mitochondrial function. Abnormal function of mitochondria was supported by decreases in respiration controlling rate (RCR), intracellular adenosine triphosphate (ATP), oxygen consumption rate, and mitochondrial membrane potential (MMP), and increases in mitochondrial reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore (mPTP), mitochondrial DNA damage, and mitochondrial respiratory chain complex enzymes. The injury of mitochondrial dynamic function was assessed by decrease in dynamin-related protein 1 (Drp1), and increases in mitofusin1/2 (Mfn1/2), and mitochondrial biogenesis injury was assessed by decreases in PPARγ coactivator-1-α (PGC-1), nucleo respiratory factor1 (Nrf1), and transcription factor A of mitochondrial (TFam). Conclusion We used isolated mitochondria from rat myocardial tissues to demonstrate that myocardial mitochondrial dysfunction occurred along with renal IR to induce myocardial cell apoptosis; obesity aggravated apoptosis. TIIA combined with CsA attenuated myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.

scholarly journals Targeting Mitochondria in Diabetes

2021 ◽  
Vol 22 (12) ◽  
pp. 6642
Author(s):  
Nina Krako Jakovljevic ◽  
Kasja Pavlovic ◽  
Aleksandra Jotic ◽  
Katarina Lalic ◽  
Milica Stoiljkovic ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Mitochondrial Function ◽  
Whole Body ◽  
Noncommunicable Diseases ◽  
Pharmacological Interventions ◽  
Cellular Energy ◽  
Cellular Energy Metabolism ◽  
Data Comparison ◽  
Selection Of

Type 2 diabetes (T2D), one of the most prevalent noncommunicable diseases, is often preceded by insulin resistance (IR), which underlies the inability of tissues to respond to insulin and leads to disturbed metabolic homeostasis. Mitochondria, as a central player in the cellular energy metabolism, are involved in the mechanisms of IR and T2D. Mitochondrial function is affected by insulin resistance in different tissues, among which skeletal muscle and liver have the highest impact on whole-body glucose homeostasis. This review focuses on human studies that assess mitochondrial function in liver, muscle and blood cells in the context of T2D. Furthermore, different interventions targeting mitochondria in IR and T2D are listed, with a selection of studies using respirometry as a measure of mitochondrial function, for better data comparison. Altogether, mitochondrial respiratory capacity appears to be a metabolic indicator since it decreases as the disease progresses but increases after lifestyle (exercise) and pharmacological interventions, together with the improvement in metabolic health. Finally, novel therapeutics developed to target mitochondria have potential for a more integrative therapeutic approach, treating both causative and secondary defects of diabetes.

scholarly journals Propofol attenuates lung ischemia/reperfusion injury though the involvement of the MALAT1/microRNA-144/GSK3β axis

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Jian-Ping Zhang ◽  
Wei-Jing Zhang ◽  
Miao Yang ◽  
Hua Fang
Keyword(s):  
Cell Apoptosis ◽  
Ischemia Reperfusion Injury ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Inflammatory Factors ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Loss Of Function

Abstract Background Propofol, an intravenous anesthetic, was proven to protect against lung ischemia/reperfusion (I/R) injury. However, the detailed mechanism of Propofol in lung I/R injury is still elusive. This study was designed to explore the therapeutic effects of Propofol, both in vivo and in vitro, on lung I/R injury and the underlying mechanisms related to metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA-144 (miR-144)/glycogen synthase kinase-3β (GSK3β). Methods C57BL/6 mice were used to establish a lung I/R injury model while pulmonary microvascular endothelial cells (PMVECs) were constructed as hypoxia/reperfusion (H/R) cellular model, both of which were performed with Propofol treatment. Gain- or loss-of-function approaches were subsequently employed, followed by observation of cell apoptosis in lung tissues and evaluation of proliferative and apoptotic capabilities in H/R cells. Meanwhile, the inflammatory factors, autophagosomes, and autophagy-related proteins were measured. Results Our experimental data revealed that Propofol treatment could decrease the elevated expression of MALAT1 following I/R injury or H/R induction, indicating its protection against lung I/R injury. Additionally, overexpressing MALAT1 or GSK3β promoted the activation of autophagosomes, proinflammatory factor release, and cell apoptosis, suggesting that overexpressing MALAT1 or GSK3β may reverse the protective effects of Propofol against lung I/R injury. MALAT1 was identified to negatively regulate miR-144 to upregulate the GSK3β expression. Conclusion Overall, our study demonstrated that Propofol played a protective role in lung I/R injury by suppressing autophagy and decreasing release of inflammatory factors, with the possible involvement of the MALAT1/miR-144/GSK3β axis.

Treatment of type 2 diabetic db/db mice with a novel PPARγ agonist improves cardiac metabolism but not contractile function

2004 ◽  
Vol 286 (3) ◽  
pp. E449-E455 ◽  
Author(s):  
Andrew N. Carley ◽  
Lisa M. Semeniuk ◽  
Yakhin Shimoni ◽  
Ellen Aasum ◽  
Terje S. Larsen ◽  
...  
Keyword(s):  
Contractile Function ◽  
Ex Vivo ◽  
Metabolic Changes ◽  
Pparγ Agonist ◽  
Perfused Hearts ◽  
Type 2 Diabetic ◽  
Contractile Performance ◽  
Exogenous Substrates

Hearts from insulin-resistant type 2 diabetic db/db mice exhibit features of a diabetic cardiomyopathy with altered metabolism of exogenous substrates and reduced contractile performance. Therefore, the effect of chronic oral administration of 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (COOH), a novel ligand for peroxisome proliferator-activated receptor-γ that produces insulin sensitization, to db/db mice (30 mg/kg for 6 wk) on cardiac function was assessed. COOH treatment reduced blood glucose from 27 mM in untreated db/db mice to a normal level of 10 mM. Insulin-stimulated glucose uptake was enhanced in cardiomyocytes from COOH-treated db/db hearts. Working perfused hearts from COOH-treated db/db mice demonstrated metabolic changes with enhanced glucose oxidation and decreased palmitate oxidation. However, COOH treatment did not improve contractile performance assessed with ex vivo perfused hearts and in vivo by echocardiography. The reduced outward K+ currents in diabetic cardiomyocytes were still attenuated after COOH. Metabolic changes in COOH-treated db/db hearts are most likely indirect, secondary to changes in supply of exogenous substrates in vivo and insulin sensitization.

scholarly journals Myocardial ischemic tolerance in rats subjected to endurance exercise training during adaptation to chronic hypoxia

2017 ◽  
Vol 122 (6) ◽  
pp. 1452-1461 ◽  
Author(s):  
Petra Alánová ◽  
Anna Chytilová ◽  
Jan Neckář ◽  
Jaroslav Hrdlička ◽  
Petra Míčová ◽  
...  
Keyword(s):  
Exercise Training ◽  
Infarct Size ◽  
Chronic Hypoxia ◽  
Ischemia Reperfusion ◽  
Ischemic Tolerance ◽  
Natural Stimuli ◽  
Size Limitation ◽  
Tnf Α ◽  
Protective Signaling

Chronic hypoxia and exercise are natural stimuli that confer sustainable cardioprotection against ischemia-reperfusion (I/R) injury, but it is unknown whether they can act in synergy to enhance ischemic resistance. Inflammatory response mediated by tumor necrosis factor-α (TNF-α) plays a role in the infarct size limitation by continuous normobaric hypoxia (CNH), whereas exercise is associated with anti-inflammatory effects. This study was conducted to determine if exercise training performed under conditions of CNH (12% O2) affects myocardial ischemic resistance with respect to inflammatory and redox status. Adult male Wistar rats were assigned to one of the following groups: normoxic sedentary, normoxic trained, hypoxic sedentary, and hypoxic trained. ELISA and Western blot analysis, respectively, were used to quantify myocardial cytokines and the expression of TNF-α receptors, nuclear factor-κB (NF-κB), and selected components of related signaling pathways. Infarct size and arrhythmias were assessed in open-chest rats subjected to I/R. CNH increased TNF-α and interleukin-6 levels and the expression of TNF-α type 2 receptor, NF-κB, inducible nitric oxide synthase (iNOS), cytosolic phospholipase A2α, cyclooxygenase-2, manganese superoxide dismutase (MnSOD), and catalase. None of these effects occurred in the normoxic trained group, whereas exercise in hypoxia abolished or significantly attenuated CNH-induced responses, except for NF-κB, iNOS, and MnSOD. Both CNH and exercise reduced infarct size, but their combination provided the same degree of protection as CNH alone. In conclusion, exercise training does not amplify the cardioprotection conferred by CNH. High ischemic tolerance of the CNH hearts persists after exercise, possibly by maintaining the increased antioxidant capacity despite attenuating TNF-α-dependent protective signaling. NEW & NOTEWORTHY Chronic hypoxia and regular exercise are natural stimuli that confer sustainable myocardial protection against acute ischemia-reperfusion injury. Signaling mediated by TNF-α via its type 2 receptor plays a role in the cardioprotective mechanism of chronic hypoxia. In the present study, we found that exercise training of rats during adaptation to hypoxia does not amplify the infarct size-limiting effect. Ischemia-resistant phenotype is maintained in the combined hypoxia-exercise setting despite exercise-induced attenuation of TNF-α-dependent protective signaling.

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