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Cited by 68Heme Oxygenase-1 and Carbon MonoxideCardiac Ischemia and ReperfusionCardiac Fibrosis and Remodeling

Heme Oxygenase-1 Induction Improves Cardiac Function following Myocardial Ischemia by Reducing Oxidative Stress

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Issan, Yossi, Kornowski, Ran, Aravot, Dan, Shainberg, Asher, Laniado-Schwartzman, Michal, Sodhi, Komal, Abraham, Nader G., Hochhauser, Edith·2014·PLoS ONE
DOI 10.1371/journal.pone.0092246PMC PMC3962395
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Abstract

BACKGROUND: Oxidative stress plays a key role in exacerbating diabetes and cardiovascular disease. Heme oxygenase-1 (HO-1), a stress response protein, is cytoprotective, but its role in post myocardial infarction (MI) and diabetes is not fully characterized. We aimed to investigate the protection and the mechanisms of HO-1 induction in cardiomyocytes subjected to hypoxia and in diabetic mice subjected to LAD ligation. METHODS: In vitro: cultured cardiomyocytes were treated with cobalt-protoporphyrin (CoPP) and tin protoporphyrin (SnPP) prior to hypoxic stress. In vivo: CoPP treated streptozotocin-induced diabetic mice were subjected to LAD ligation for 2/24 h. Cardiac function, histology, biochemical damage markers and signaling pathways were measured. RESULTS: HO-1 induction lowered release of lactate dehydrogenase (LDH) and creatine phospho kinase (CK), decreased propidium iodide staining, improved cell morphology and preserved mitochondrial membrane potential in cardiomyocytes. In diabetic mice, Fractional Shortening (FS) was lower than non-diabetic mice (35±1%vs.41±2, respectively p<0.05). CoPP-treated diabetic animals improved cardiac function (43±2% p<0.01), reduced CK, Troponin T levels and infarct size compared to non-treated diabetic mice (P<0.01, P<0.001, P<0.01 respectively). CoPP-enhanced HO-1 protein levels and reduced oxidative stress in diabetic animals, as indicated by the decrease in superoxide levels in cardiac tissues and plasma TNFα levels (p<0.05). The increased levels of HO-1 by CoPP treatment after LAD ligation led to a shift of the Bcl-2/bax ratio towards the antiapoptotic process (p<0.05). CoPP significantly increased the expression levels of pAKT and pGSK3β (p<0.05) in cardiomyocytes and in diabetic mice with MI. SnPP abolished CoPP's cardioprotective effects. CONCLUSIONS: HO-1 induction plays a role in cardioprotection against hypoxic damage in cardiomyocytes and in reducing post ischemic cardiac damage in the diabetic heart as proved by the increased levels of pAKT with a concomitant inhibition of pGSK3β leading to preserved mitochondrial membrane potential.

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  • Low plasma levels of adiponectin seen in diabetes contribute to the oxidative damage seen in DCM.

    “Adiponectin is a hormone secreted by adipose tissue that regulates metabolic processes and functions as an antioxidant; the low plasma levels of adiponectin seen in diabetes contribute to the oxidative damage seen in DCM [24, 25].”

    From Role of Serum Biomarkers in Early Detection of Diabetic Cardiomyopathy in the West Virginian Population (2016) · cites this paper as [25]

    The Results section on oxidative stress in diabetic mouse hearts reports elevated cardiac superoxide and lower circulating adiponectin in untreated diabetic mice than in CoPP-treated diabetic mice. The Discussion describes adiponectin as beneficial to the heart, but the paper does not establish that low adiponectin causes oxidative damage in diabetic cardiomyopathy (DCM); its cardiac experiments concern myocardial ischemia after LAD ligation. No page numbers are available in our copy. (LLM, conf=0.85)

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Research works printed but not linked: 42

  1. [1]Tompkins AJ, Burwell LS, Digerness SB, Zaragoza C, Holman WL, et al (2006) Mitochondrial dysfunction in cardiac ischemia-reperfusion injury: ROS from complex I, without inhibition. Biochim Biophys Acta 1762: 223– 231. 16278076
  2. [2]Hunter DR, Haworth RA (1979) The Ca2+-induced membrane transition in mitochondria. III. Transitional Ca2+ release. Arch Biochem Biophys 195: 468– 477. 112926
  3. [3]Crompton M, Costi A, Hayat L (1987) Evidence for the presence of a reversible Ca2+-dependent pore activated by oxidative stress in heart mitochondria. Biochem J 245: 915– 918. 3117053 PMC1148218
  4. [4]Crompton M (1999) The mitochondrial permeability transition pore and its role in cell death. Biochem J 341 (Pt 2): 233– 249. 10393078 PMC1220352
  5. [5]Halestrap AP (1999) The mitochondrial permeability transition: its molecular mechanism and role in reperfusion injury. Biochem Soc Symp 66: 181– 203. 10989667
  6. [6]Halestrap AP, McStay GP, Clarke SJ (2002) The permeability transition pore complex: another view. Biochimie 84: 153– 166. 12022946
  7. [7]Abraham NG, Tsenovoy PL, McClung J, Drummond GS (2008) Heme oxygenase: a target gene for anti-diabetic and obesity. Curr Pharm Des 14: 412– 421. 18289068
  8. [8]Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN (1987) Bilirubin is an antioxidant of possible physiological importance. Science 235: 1043– 1046. 3029864
  9. [9]Hill-Kapturczak N, Chang SH, Agarwal A (2002) Heme oxygenase and the kidney. DNA Cell Biol 21: 307– 321. 12042070
  10. [10]L'Abbate A, Neglia D, Vecoli C, Novelli M, Ottaviano V, et al (2007) Beneficial effect of heme oxygenase-1 expression on myocardial ischemia-reperfusion involves an increase in adiponectin in mildly diabetic rats. Am J Physiol Heart Circ Physiol 293: H3532– 3541. 17906103
  11. [11]Kruger AL, Peterson S, Turkseven S, Kaminski PM, Zhang FF, et al (2005) D-4F induces heme oxygenase-1 and extracellular superoxide dismutase, decreases endothelial cell sloughing, and improves vascular reactivity in rat model of diabetes. Circulation 111: 3126– 3134. 15939814
  12. [12]Issan Y, Hochhauser E, Kornowski R, Leshem-Lev D, Lev E, et al (2012) Endothelial progenitor cell function inversely correlates with long-term glucose control in diabetic patients: association with the attenuation of the heme oxygenase-adiponectin axis. Can J Cardiol 28: 728– 736. 22445099 PMC5554949
  13. [13]Hosick PA, Stec DE (2012) Heme oxygenase, a novel target for the treatment of hypertension and obesity? Am J Physiol Regul Integr Comp Physiol 302: R207– 214. 22071158 PMC3349392
  14. [14]Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, et al (2000) Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20: 1595– 1599. 10845877
  15. [15]Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF (1995) A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270: 26746– 26749. 7592907
  16. [18]Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, et al (2002) Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 106: 2767– 2770. 12451000
  17. [20]Berg AH, Scherer PE (2005) Adipose tissue, inflammation, and cardiovascular disease. Circ Res 96: 939– 949. 15890981
  18. [21]Reilly MP, Rader DJ (2003) The metabolic syndrome: more than the sum of its parts? Circulation 108: 1546– 1551. 14517150
  19. [23]Hochhauser E, Cheporko Y, Yasovich N, Pinchas L, Offen D, et al (2007) Bax deficiency reduces infarct size and improves long-term function after myocardial infarction. Cell Biochem Biophys 47: 11– 20. 17406056
  20. [24]Shneyvays V, Leshem D, Zinman T, Mamedova LK, Jacobson KA, et al (2005) Role of adenosine A1 and A3 receptors in regulation of cardiomyocyte homeostasis after mitochondrial respiratory chain injury. Am J Physiol Heart Circ Physiol 288: H2792– 2801. 15681707 PMC3457058
  21. [25]Shmist YA, Kamburg R, Ophir G, Kozak A, Shneyvays V, et al (2005) N,N,N',N'-tetrakis(2-pyridylmethyl)-ethylenediamine improves myocardial protection against ischemia by modulation of intracellular Ca2+ homeostasis. J Pharmacol Exp Ther 313: 1046– 1057. 15681657
  22. [26]Emanuelov AK, Shainberg A, Chepurko Y, Kaplan D, Sagie A, et al (2010) Adenosine A3 receptor-mediated cardioprotection against doxorubicin-induced mitochondrial damage. Biochem Pharmacol 79: 180– 187. 19686702
  23. [27]Hochhauser E, Kivity S, Offen D, Maulik N, Otani H, et al (2003) Bax ablation protects against myocardial ischemia-reperfusion injury in transgenic mice. Am J Physiol Heart Circ Physiol 284: H2351– 2359. 12742833
  24. [28]Li M, Kim DH, Tsenovoy PL, Peterson SJ, Rezzani R, et al (2008) Treatment of obese diabetic mice with a heme oxygenase inducer reduces visceral and subcutaneous adiposity, increases adiponectin levels, and improves insulin sensitivity and glucose tolerance. Diabetes 57: 1526– 1535. 18375438
  25. [29]Toshima S, Hasegawa A, Kurabayashi M, Itabe H, Takano T, et al (2000) Circulating oxidized low density lipoprotein levels. A biochemical risk marker for coronary heart disease. Arterioscler Thromb Vasc Biol 20: 2243– 2247. 11031210
  26. [31]Borger DR, Essig DA (1998) Induction of HSP 32 gene in hypoxic cardiomyocytes is attenuated by treatment with N-acetyl-L-cysteine. Am J Physiol 274: H965– 973. 9530210
  27. [32]Cai C, Teng L, Vu D, He JQ, Guo Y, et al (2012) The heme oxygenase 1 inducer (CoPP) protects human cardiac stem cells against apoptosis through activation of the extracellular signal-regulated kinase (ERK)/NRF2 signaling pathway and cytokine release. J Biol Chem 287: 33720– 33732. 22879597 PMC3460469
  28. [33]Kawamoto S, Flynn JP, Shi Q, Sakr SW, Luo J, et al (2011) Heme oxygenase-1 induction enhances cell survival and restores contractility to unvascularized three-dimensional adult cardiomyocyte grafts implanted in vivo. Tissue Eng Part A 17: 1605– 1614. 21288159 PMC3098958
  29. [34]Sardana MK, Kappas A (1987) Dual control mechanism for heme oxygenase: tin(IV)-protoporphyrin potently inhibits enzyme activity while markedly increasing content of enzyme protein in liver. Proc Natl Acad Sci U S A 84: 2464– 2468. 3470805 PMC304672
  30. [35]Tilg H, Moschen AR (2006) Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6: 772– 783. 16998510
  31. [36]Zhu W, Cheng KK, Vanhoutte PM, Lam KS, Xu A (2008) Vascular effects of adiponectin: molecular mechanisms and potential therapeutic intervention. Clin Sci (Lond) 114: 361– 374. 18230060
  32. [37]Xu A, Vanhoutte PM (2010) Adiponectin and adipocyte fatty acid binding protein in the pathogenesis of cardiovascular disease. Am J Physiol Heart Circ Physiol 302: H1231– 1240. 22210749
  33. [38]Sharma HS, Maulik N, Gho BC, Das DK, Verdouw PD (1996) Coordinated expression of heme oxygenase-1 and ubiquitin in the porcine heart subjected to ischemia and reperfusion. Mol Cell Biochem 157: 111– 116. 8739236
  34. [39]Melo LG, Agrawal R, Zhang L, Rezvani M, Mangi AA, et al (2002) Gene therapy strategy for long-term myocardial protection using adeno-associated virus-mediated delivery of heme oxygenase gene. Circulation 105: 602– 607. 11827926
  35. [40]Abraham NG, Rezzani R, Rodella L, Kruger A, Taller D, et al (2004) Overexpression of human heme oxygenase-1 attenuates endothelial cell sloughing in experimental diabetes. Am J Physiol Heart Circ Physiol 287: H2468– 2477. 15284058
  36. [41]Abraham NG, Kappas A (2008) Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev 60: 79– 127. 18323402
  37. [42]Kleschyov AL, Wendt M, Munzel T (2002) Heme oxygenase-1-mediated protection: potential role of nonheme iron-nitric oxide complexes. Circulation 105: e196; author reply e196. 12082007
  38. [43]Hori R, Kashiba M, Toma T, Yachie A, Goda N, et al (2002) Gene transfection of H25A mutant heme oxygenase-1 protects cells against hydroperoxide-induced cytotoxicity. J Biol Chem 277: 10712– 10718. 11786534
  39. [44]Kusmic C, L'Abbate A, Sambuceti G, Drummond G, Barsanti C, et al (2010) Improved myocardial perfusion in chronic diabetic mice by the up-regulation of pLKB1 and AMPK signaling. J Cell Biochem 109: 1033– 1044. 20108250 PMC3723413
  40. [45]Juhaszova M, Zorov DB, Yaniv Y, Nuss HB, Wang S, et al (2009) Role of glycogen synthase kinase-3beta in cardioprotection. Circ Res 104: 1240– 1252. 19498210 PMC2726042
  41. [46]Javadov S, Karmazyn M, Escobales N (2009) Mitochondrial permeability transition pore opening as a promising therapeutic target in cardiac diseases. J Pharmacol Exp Ther 330: 670– 678. 19509316
  42. [47]Quarrie R, Lee DS, Steinbaugh G, Cramer B, Erdahl W, et al (2012) Ischemic preconditioning preserves mitochondrial membrane potential and limits reactive oxygen species production. J Surg Res 178: 8– 17. 22763215 PMC3470827

Cited by

Sorted by citations

Authors
Issan, Y., Kornowski, R., Aravot, D., Shainberg, A., Laniado-Schwartzman, M., Sodhi, K., Abraham, N. G., & Hochhauser, E.
Affiliations
  • Tel Aviv University (IL)
  • Bar-Ilan University (IL)
  • Marshall University (US)
Corresponding author
Hochhauser, Edith
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2014-03-21
Volume
9
Issue
3
Pages
e92246
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0092246
PMC
PMC3962395
OpenAlex
W2019210320
Cited by
68
References
5
Citations by year
2025: 1 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 10 · 2019: 8 · 2018: 14 · 2017: 3 · 2016: 11 · 2015: 8 · 2014: 3
FWCI
3.42
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Touro Scholar (Touro College) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (HL-34300)
  • National Heart, Lung, and Blood Institute (P01HL034300, HL 34300)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK056601, DK56601)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
heme oxygenase-1, myocardial ischemia, diabetes mellitus, oxidative stress, cardiomyocyte hypoxia, cobalt protoporphyrin, tin protoporphyrin, cardiac function, apoptosis, Bcl-2/Bax ratio, Akt signaling, GSK3β, superoxide, TNF-α, myocardial infarct size, streptozotocin-induced diabetes
MeSH terms
Animals, Cells, Cultured, Diabetes Mellitus, Experimental, Enzyme Induction, Male, Metalloporphyrins, Mice, Inbred C57BL, Myocardial Infarction, Protoporphyrins, Myocardial Ischemia, Rats, Sprague-Dawley, Oxidative Stress, Myocytes, Cardiac, Proto-Oncogene Proteins c-akt, Heme Oxygenase-1, Membrane Potential, Mitochondrial

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