Protective role of heme oxygenase-1 in atrial remodeling

Yeh, Yung‐Hsin; Hsu, Lung‐An; Chen, Ying‐Hwa; Kuo, Chi-Tai; Chang, Gwo‐Jyh; Chen, Wen‐Jone

doi:10.1007/s00395-016-0577-y

Cited by 30 publications

(29 citation statements)

References 44 publications

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“…Increased ROS levels can damage proteins, lipids, and DNA (especially mitochondria DNA), and induce inflammation by augmenting cytokine production from activated inflammatory cells, which, in turn, precipitates further tissue damage . In addition, ROS are involved in cardiac structural and electrical remodeling, which increase the susceptibility to AF . In our study, the content of lipid oxidation products MDA and DNA oxidation products 8‐OHdG were sharply raised in the circulation of diabetic rabbits, providing indirect evidence that increased oxidative stress is involved.…”

Section: Discussionsupporting

confidence: 52%

Alogliptin, a Dipeptidyl Peptidase‐4 Inhibitor, Alleviates Atrial Remodeling and Improves Mitochondrial Function and Biogenesis in Diabetic Rabbits

Zhang

Zhao

et al. 2017

JAHA

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BackgroundThere is increasing evidence implicating atrial mitochondrial dysfunction in the pathogenesis of atrial fibrillation. In this study, we explored whether alogliptin, a dipeptidyl peptidase‐4 inhibitor, can prevent mitochondrial dysfunction and atrial remodeling in a diabetic rabbit model.Methods and ResultsA total of 90 rabbits were randomized into 3 groups as follows: control group (n=30), alloxan‐induced diabetes mellitus group (n=30), and alogliptin‐treated (12.5 mg/kg per day for 8 weeks) diabetes mellitus group (n=30). Echocardiographic and hemodynamic assessments were performed in vivo. The serum concentrations of glucagon‐like peptide‐1, insulin, and inflammatory and oxidative stress markers were measured. Electrophysiological properties of Langendorff‐perfused rabbit hearts were assessed. Mitochondrial morphology, respiratory function, membrane potential, and reactive oxygen species generation rate were assessed. The protein expression of transforming growth factor β1, nuclear factor κB p65, and mitochondrial biogenesis–related proteins were measured by Western blot analysis. Diabetic rabbits exhibited left ventricular hypertrophy and left atrial dilation without obvious hemodynamic abnormalities, and all of these changes were attenuated by alogliptin. Compared with the control group, higher atrial fibrillation inducibility in the diabetes mellitus group was observed, and markedly reduced by alogliptin. Alogliptin decreased mitochondrial reactive oxygen species production rate, prevented mitochondrial membrane depolarization, and alleviated mitochondrial swelling in diabetic rabbits. It also improved mitochondrial biogenesis by peroxisome proliferator–activated receptor‐γ coactivator 1α/nuclear respiratory factor‐1/mitochondrial transcription factor A signaling regulated by adiponectin/AMP‐activated protein kinase.ConclusionsDipeptidyl peptidase‐4 inhibitors can prevent atrial fibrillation by reversing electrophysiological abnormalities, improving mitochondrial function, and promoting mitochondrial biogenesis.

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Section: Discussionsupporting

confidence: 52%

Alogliptin, a Dipeptidyl Peptidase‐4 Inhibitor, Alleviates Atrial Remodeling and Improves Mitochondrial Function and Biogenesis in Diabetic Rabbits

Zhang

Zhao

et al. 2017

JAHA

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“…Hmox1 was previously described as vulnerable atherosclerotic plaque defining agent [6] and its overexpression with gene therapy decreased interstitial collagen in rat hearts exposed to I/R injury [32]. Moreover, it was recently shown that Hmox1 −/− mice exhibit a higher than WT mice degree of collagen deposition in their atria [52]. To the best of our knowledge, here we report for the first time that the lack of Hmox1 significantly lowers the risk of LVFWR after permanent LAD ligation.…”

Section: Discussionmentioning

confidence: 99%

Splenic Ly6Chi monocytes contribute to adverse late post-ischemic left ventricular remodeling in heme oxygenase-1 deficient mice

et al. 2017

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Heme oxygenase-1 (Hmox1) is a stress-inducible protein crucial in heme catabolism. The end products of its enzymatic activity possess anti-oxidative, anti-apoptotic and anti-inflammatory properties. Cardioprotective effects of Hmox1 were demonstrated in experimental models of myocardial infarction (MI). Nevertheless, its importance in timely resolution of post-ischemic inflammation remains incompletely understood. The aim of this study was to determine the role of Hmox1 in the monocyte/macrophage-mediated cardiac remodeling in a mouse model of MI. Hmox1 knockout (Hmox1−/−) and wild-type (WT, Hmox1+/+) mice were subjected to a permanent ligation of the left anterior descending coronary artery. Significantly lower incidence of left ventricle (LV) free wall rupture was noted between 3rd and 5th day after MI in Hmox1−/− mice resulting in their better overall survival. Then, starting from 7th until 21st day post-MI a more potent deterioration of LV function was observed in Hmox1−/− than in the surviving Hmox1+/+ mice. This was accompanied by higher numbers of Ly6Chi monocytes in peripheral blood, as well as higher expression of monocyte chemoattractant protein-1 and adhesion molecules in the hearts of MI-operated Hmox1−/− mice. Consequently, a greater post-MI monocyte-derived myocardial macrophage infiltration was noted in Hmox1-deficient individuals. Splenectomy decreased the numbers of circulating inflammatory Ly6Chi monocytes in blood, reduced the numbers of proinflammatory cardiac macrophages and significantly improved the post-MI LV function in Hmox1−/− mice. In conclusion, Hmox1 deficiency has divergent consequences in MI. On the one hand, it improves early post-MI survival by decreasing the occurrence of cardiac rupture. Afterwards, however, the hearts of Hmox1-deficient mice undergo adverse late LV remodeling due to overactive and prolonged post-ischemic inflammatory response. We identified spleen as an important source of these cardiovascular complications in Hmox1−/− mice.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-017-0629-y) contains supplementary material, which is available to authorized users.

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“…Detection of NADPH-Dependent Superoxide Production by Chemiluminescence. Generation of superoxide was estimated in fresh LV tissue (approximately 2 mg) with lucigenin-enhanced chemiluminescence using a luminometer (Plate CHAMELEON; Hidex, Turku, Finland) as described elsewhere (Yeh et al, 2016). Photon outputs were measured after addition of lucigenin (5 mM) and NADPH (100 mM).…”

Section: Methodsmentioning

confidence: 99%

“…In Vitro Transfection of Small Interfering RNA. HL-1 atrial myocytes in four-well dishes were transfected with chemically synthesized small interfering RNAs (siRNAs) for RAGE, or its control siRNA (200 nM/well; Dharmacon, Lafayette, CO) for 48 hours before cell treatment using DharmaFECT 1 (Dharmacon) according to the manufacturer's instructions (Yeh et al, 2016). The on-target siRNAsmart pool included four sequences.…”

Section: Methodsmentioning

confidence: 99%

“…Detection of Intracellular Reactive Oxygen Species. Intracellular reactive oxygen species (ROS) generation in HL-1 cells was measured using cell-permeable fluorescent dyes (2,7-dichlorodihydrofluorescein diacetate or dihydroethidium) at a concentration of 10 mM (Yeh et al, 2016). The ROS-mediated fluorescence was observed under a confocal microscope (TCS SP2; Leica, Wetzlar, Germany) with excitation using a 488-nm argon laser.…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of Advanced Glycation End Products Formation Attenuates Cardiac Electrical and Mechanical Remodeling and Vulnerability to Tachyarrhythmias in Diabetic Rats

Chang

Yeh

Chen

et al. 2018

J Pharmacol Exp Ther

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Diabetic patients with cardiomyopathy show a higher incidence of arrhythmias and sudden death. Chronic hyperglycemia induces the formation of advanced glycation end products (AGEs), which contribute to the pathogenesis of diabetic cardiomyopathy. This study investigated whether inhibition of AGEs formation by aminoguanidine (AG) could prevent cardiac electromechanical and arrhythmogenic remodeling in diabetes mellitus. Streptozotocininduced diabetic rats received AG (100 mg/kg daily, i.p.) or vehicle (normal saline, i.p.) for 5 weeks. The rats underwent hemodynamic recording to evaluate cardiac function, and heart preparations were used to determine the electrical, mechanical, and biochemical functions. In vitro high glucose-induced AGEs formation, reactive oxygen species (ROS) generation, and action potential changes were examined in HL-1 atrial cells. AG treatment improved the diabetes-induced depression in left ventricular pressure and the relaxation rate, and normalized the prolongation of QTc intervals in anesthetized rats. AG reduced the vulnerabilities to atrial and ventricular tachyarrhythmias in perfused diabetic hearts. AG normalized the prolonged action potential duration in diabetic atrial and ventricular muscles, which was correlated with the restoration of both transient outward (I to ) and steady-state outward (I SS ) K 1 current densities in cardiomyocytes. The abnormal kinetics of Ca 21 transients and contraction were reversed in cardiomyocytes from AG-treated diabetic rats, along with parallel preservation of sarco(endo)plasmic reticulum Ca 21 -ATPase (SERCA2a) expression. Furthermore, ex vivo and in vitro studies showed AG attenuated AGEs and ROS formation. Thus, long-term administration of AG ameliorated cardiac electromechanical remodeling and arrhythmogenicity in diabetic rats and may present an effective strategy for the prevention of diabetes-associated arrhythmias.s This article has supplemental material available at jpet.aspetjournals.org.ABBREVIATIONS: AERP, atrial effective refractory period; AG, aminoguanidine; AGE, advanced glycation end product; APD 25 , 50, 90 , action potential duration measured at 25%, 50%, and 90% repolarization; AT, atrial tachyarrhythmias; BW, body weight; DM, diabetes mellitus; dP/dt max and dP/dt min , maximal rate of rise and fall of LV

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Protective role of heme oxygenase-1 in atrial remodeling

Cited by 30 publications

References 44 publications

Alogliptin, a Dipeptidyl Peptidase‐4 Inhibitor, Alleviates Atrial Remodeling and Improves Mitochondrial Function and Biogenesis in Diabetic Rabbits

Alogliptin, a Dipeptidyl Peptidase‐4 Inhibitor, Alleviates Atrial Remodeling and Improves Mitochondrial Function and Biogenesis in Diabetic Rabbits

Splenic Ly6Chi monocytes contribute to adverse late post-ischemic left ventricular remodeling in heme oxygenase-1 deficient mice

Inhibition of Advanced Glycation End Products Formation Attenuates Cardiac Electrical and Mechanical Remodeling and Vulnerability to Tachyarrhythmias in Diabetic Rats

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