Diabetes Exacerbates Myocardial Ischemia/Reperfusion Injury by Down-Regulation of MicroRNA and Up-Regulation of O-GlcNAcylation

Wang, Dandan; Hu, Xiaoyue; Lee, Seung Hee; Chen, Feng; Jiang, Kai; Tu, Zizhuo; Liu, Zejian; Du, Jing; Wang, Li; Yin, Chaoying; Liu, Yu; Shang, Hongcai; Martin, Kathleen A.; Herzog, Raimund I.; Young, Lawrence H.; Li, Qian; Hwa, John; Xiang, Yaozu

doi:10.1016/j.jacbts.2018.01.005

Cited by 41 publications

(42 citation statements)

References 46 publications

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“…In the db / db genetic model of T2D, Wang et al. () report reduced I–R tolerance, attributing this to a fall in miR‐24, which protects healthy and db / db hearts when overexpressed (though whether normalising I–R tolerance across groups was not tested). Our findings also agree with those of Hjortbak et al.…”

Section: Discussionmentioning

confidence: 99%

Chronic type 2 but not type 1 diabetes impairs myocardial ischaemic tolerance and preconditioning in C57Bl/6 mice

Russell

Griffith

Helman

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?What is the impact of chronic adult‐onset diabetes on cardiac ischaemic outcomes and preconditioning? What is the main finding and its importance?Chronic adult‐onset type 2 but not type 1 diabetes significantly impairs myocardial ischaemic tolerance and ischaemic preconditioning. Preconditioning may be detrimental in type 2 diabetes, exaggerating nitrosative stress and apoptotic protein expression. Abstract Effects of diabetes on myocardial responses to ischaemia–reperfusion (I–R) and cardioprotective stimuli remain contentious, potentially reflecting influences of disease duration and time of onset. Chronic adult‐onset type 1 diabetes (T1D) and type 2 diabetes (T2D) were modelled non‐genetically in male C57Bl/6 mice via 5 × 50 mg kg−1 daily streptozotocin (STZ) injections + 12 weeks’ standard chow or 1 × 75 mg kg−1 STZ injection + 12 weeks’ obesogenic diet (32% calories as fat, 57% carbohydrate, 11% protein), respectively. Systemic outcomes were assessed and myocardial responses to I–R ± ischaemic preconditioning (IPC; 3 × 5 min I–R) determined in Langendorff perfused hearts. Uncontrolled T1D was characterised by pronounced hyperglycaemia (25 mm fasting glucose), glucose intolerance and ∼10% body weight loss, whereas T2D mice exhibited moderate hyperglycaemia (15 mm), hyperinsulinaemia, glucose intolerance and 17% weight gain. Circulating ghrelin, resistin and noradrenaline were unchanged with T1D, while leptin increased and noradrenaline declined in T2D mice. Ischaemic tolerance and IPC were preserved in T1D hearts. In contrast, T2D worsened post‐ischaemic function (∼40% greater diastolic and contractile dysfunction) and cell death (100% higher troponin efflux), and abolished IPC protection. Whereas IPC reduced post‐ischaemic nitrotyrosine and pro‐apoptotic Bak and Bax levels in non‐diabetic hearts, these effects were reduced in T1D and IPC augmented Bax and nitrosylation in T2D hearts. The data demonstrate chronic T1D does not inhibit myocardial I–R tolerance or IPC, whereas metabolic and endocrine disruption in T2D is associated with ischaemic intolerance and inhibition of IPC. Indeed, normally protective IPC may exaggerate damage mechanisms in T2D hearts.

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Section: Discussionmentioning

confidence: 99%

Chronic type 2 but not type 1 diabetes impairs myocardial ischaemic tolerance and preconditioning in C57Bl/6 mice

Russell

Griffith

Helman

et al. 2019

Experimental Physiology

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“…Caveolin-1 may also be protective [67], whereas cavin-4 appears to limit cardiac stress-resistance [70]. Prior studies indicate ALA may augment caveolin-3 in cardiomyocytes and cardiomyopathic hearts [46], and counters both inflammation-dependent down-regulation of skeletal myoblast caveolin-3 [60] and up-regulation of endothelial caveolin-1 [115]. Other data indicate n-3 PUFA intake suppresses vascular caveolin-1, albeit in a model of experimental menopause [62].…”

Section: Caveolar Protein Expression and Localizationmentioning

confidence: 99%

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

et al. 2020

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Whether dietary omega-3 (n-3) polyunsaturated fatty acid (PUFA) confers cardiac benefit in cardiometabolic disorders is unclear. We test whether dietary -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-3 β (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.

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“…Diabetic patients endure increased mortality following acute myocardial infarction 1 . Conventional preconditioning (short-term ischemic episodes before an extended ischemic period) has been extensively studied in hearts achieved from animals and patients.…”

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confidence: 99%

Sevoflurane Pre-conditioning Ameliorates Diabetic Myocardial Ischemia/Reperfusion Injury Via Differential Regulation of p38 and ERK

Xie

Zhao

Guo

et al. 2020

Sci Rep

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Diabetes mellitus (DM) significantly increases myocardial ischemia/reperfusion (MI/R) injury. During DM, cardioprotection induced by conventional pre-conditioning (PreCon) is decreased due to impaired AMP-activated protein kinase (AMPK) signaling. The current study investigated whether PreCon with inhaled anesthetic sevoflurane (SF-PreCon) remains cardioprotective during DM, and identified the involved mechanisms. Normal diet (ND) and high-fat diet (HFD)-induced DM mice were randomized into control and SF-PreCon (3 cycles of 15-minute period exposures to 2% sevoflurane) groups before MI/R. SF-PreCon markedly reduced MI/R injury in DM mice, as evidenced by improved cardiac function (increased LVEF and ±Dp/dt), decreased infarct size, and decreased apoptosis. To determine the relevant role of AMPK, the effect of SF-PreCon was determined in cardiac-specific AMPKα2 dominant negative expressing mice (AMPK-DN). SF-PreCon decreased MI/R injury in AMPK-DN mice. To explore the molecular mechanisms responsible for SF-PreCon mediated cardioprotection in DM mice, cell survival molecules were screened. Interestingly, in ND mice, SF-PreCon significantly reduced MI/Rinduced activation of p38, a pro-death MAPK, without altering ERK and JNK. In DM and AMPK-DN mice, the inhibitory effect of SF-PreCon upon p38 activation was significantly blunted. However, SF-PreCon significantly increased phosphorylation of ERK1/2, a pro-survival MAPK in DM and AMPK-DN mice. We demonstrate that SF-PreCon protects the heart via AMPK-dependent inhibition of pro-death MAPK in ND mice. However, SF-PreCon exerts cardioprotective action via AMPK-independent activation of a pro-survival MAPK member in DM mice. SF-PreCon may be beneficial compared to conventional PreCon in diabetes or clinical scenarios in which AMPK signaling is impaired.

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Diabetes Exacerbates Myocardial Ischemia/Reperfusion Injury by Down-Regulation of MicroRNA and Up-Regulation of O-GlcNAcylation

Abstract: Visual Abstract

Cited by 41 publications

References 46 publications

Chronic type 2 but not type 1 diabetes impairs myocardial ischaemic tolerance and preconditioning in C57Bl/6 mice

Chronic type 2 but not type 1 diabetes impairs myocardial ischaemic tolerance and preconditioning in C57Bl/6 mice

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

Sevoflurane Pre-conditioning Ameliorates Diabetic Myocardial Ischemia/Reperfusion Injury Via Differential Regulation of p38 and ERK

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