Combinatorial therapy of exercise-preconditioning and nanocurcumin formulation supplementation improves cardiac adaptation under hypobaric hypoxia
-
Sarita Nehra
Abstract
Background:
Chronic hypobaric hypoxia (cHH) mediated cardiac insufficiencies are associated with pathological damage. Sustained redox stress and work load are major causative agents of cardiac insufficiencies under cHH. Despite the advancements made in pharmacological (anti-oxidants, vasodilators) and non-pharmacological therapeutics (acclimatization strategies and schedules), only partial success has been achieved in improving cardiac acclimatization to cHH. This necessitates the need for potent combinatorial therapies to improve cardiac acclimatization at high altitudes. We hypothesize that a combinatorial therapy comprising preconditioning to mild aerobic treadmill exercise and supplementation with nanocurcumin formulation (NCF) consisting of nanocurcumin (NC) and pyrroloquinoline quinone (PQQ) might improve cardiac adaptation at high altitudes.
Methods:
Adult Sprague-Dawley rats pre-conditioned to treadmill exercise and supplemented with NCF were exposed to cHH (7620 m altitude corresponding to pO2~8% at 28±2°C, relative humidity 55%±1%) for 3 weeks. The rat hearts were analyzed for changes in markers of oxidative stress (free radical leakage, lipid peroxidation, manganese-superoxide dismutase [MnSOD] activity), cardiac injury (circulating cardiac troponin I [TnI] and T [cTnT], myocardial creatine kinase [CK-MB]), metabolic damage (lactate dehydrogenase [LDH] and acetyl-coenzyme A levels, lactate and pyruvate levels) and bio-energetic insufficiency (ATP, p-AMPKα).
Results:
Significant modulations (p≤0.05) in cardiac redox status, metabolic damage, cardiac injury and bio-energetics were observed in rats receiving both NCF supplementation and treadmill exercise-preconditioning compared with rats receiving only one of the treatments.
Conclusions:
The combinatorial therapeutic strategy showed a tremendous improvement in cardiac acclimatization to cHH compared to either exercise-preconditioning or NCF supplementation alone which was evident from the effective modulation in redox, metabolic, contractile and bio-energetic homeostasis.
Acknowledgments
The authors sincerely thank the Director, Defence Institute of Physiology and Allied Science, for facilitating the necessary resources for conducting the present study.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: The present work was funded by Defence Research and Development Organization, Ministry of Defence, Government of India.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Pokreisz P, Marsboom G, Janssens S. Pressure overload-induced right ventricular dysfunction and remodelling in experimental pulmonary hypertension the right heart revisited. Eur Heart J 2007;9:H57–84.10.1093/eurheartj/sum021Search in Google Scholar
2. Berenji K, Drazner MH, Rothermel BA, Hill JA. Does load-induced ventricular hypertrophy progress to systolic heart failure? Am J Physiol Heart Circ Physiol 2005;289:H8–16.10.1152/ajpheart.01303.2004Search in Google Scholar PubMed
3. Nehra S, Bhardwaj V, Kalra N, Ganju L, Bansal A, Saxena S, et al. Nanocurcumin protects cardiomyoblasts H9c2 from hypoxia-induced hypertrophy and apoptosis by improving oxidative balance. J Physiol Biochem 2015;71:239–51.10.1007/s13105-015-0405-0Search in Google Scholar PubMed
4. Nehra S, Bhardwaj V, Ganju L, Saraswat D. Nanocurcumin prevents hypoxia induced stress in primary human ventricular cardiomyocytes by maintaining mitochondrial homeostasis. PLoS One 2015;10:e0139121:1–26.10.1371/journal.pone.0139121Search in Google Scholar PubMed PubMed Central
5. Ventura-clapier R, Mettauer B, Bigard X. Beneficial effects of endurance training on cardiac and skeletal muscle energy metabolism in heart failure. Cardiovasc Res 2007;73:10–8.10.1016/j.cardiores.2006.09.003Search in Google Scholar PubMed
6. Nehra S, Bhardwaj V, Kar S, Saraswat D. Chronic hypobaric hypoxia induces right ventricular hypertrophy and apoptosis in rats: therapeutic potential of nanocurcumin in improving adaptation. High Alt Med Biol 2016;17:342–52.10.1089/ham.2016.0032Search in Google Scholar PubMed
7. Hainsworth R, Drinkhill MJ. Cardiovascular adjustments for life at high altitude. Respir Physiol Neurobiol 2007;158: 204–11.10.1016/j.resp.2007.05.006Search in Google Scholar PubMed
8. Penaloza D, Arias-Stella J. The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness. Circulation 2007;115:1132–46.10.1161/CIRCULATIONAHA.106.624544Search in Google Scholar PubMed
9. León-Velarde F, Maggiorini M, Reeves JT, Aldashev A, Asmus I, Bernardi L, et al. Consensus statement on chronic and subacute high altitude diseases. High Alt Med Biol 2005:6:147–57.10.1089/ham.2005.6.147Search in Google Scholar PubMed
10. Oscai LB, Mole PA, Holloszy JO. Effects of exercise on cardiac weight and mitochondria in male and female rats. Am J Physiol 1971;220:1944–8.10.1152/ajplegacy.1971.220.6.1944Search in Google Scholar PubMed
11. Ostadal B, Ostadalova I, Dhalla NS. Development of cardiac sensitivity to oxygen deficiency: comparative and ontogenetic aspects. Physiol Rev 1999;79:635–59.10.1152/physrev.1999.79.3.635Search in Google Scholar
12. Scheuer J, Tipton CM. Cardiovascular adaptations to physical training. Annu Rev Physiol 1977;39:221–51.10.1146/annurev.ph.39.030177.001253Search in Google Scholar
13. Bakonyi T, Radak Z. High altitude and free radicals. J Sport Sci Med 2004;3:64–9.Search in Google Scholar
14. Aaron CP, Tandri H, Barr RG, Johnson WC, Bagiella E, Chahal H, et al. Physical activity and right ventricular structure and function. The MESA-right ventricle study. Am J Respir Crit Care Med 2011;183:396–404.10.1164/ajrccm-conference.2009.179.1_MeetingAbstracts.A4146Search in Google Scholar
15. Wei JY, Li Y, Lincoln T, Grossman W, Mendelowitz D. Chronic exercise training protects aged cardiac muscle against hypoxia. J Clin Invest 1989;83:778–84.10.1172/JCI113957Search in Google Scholar
16. Belardinelli R, Georgiou D, Scocco V, Barstow TJ, Purcaro A. Low intensity exercise training in patients with chronic heart failure. J Am Coll Cardiol 1995;26:975–82.10.1016/0735-1097(95)00267-1Search in Google Scholar
17. Giordano FJ. Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest 2005;115:500–8.10.1172/JCI200524408Search in Google Scholar
18. Nehra S, Bhardwaj V, Bansal A, Saraswat D. Nanocurcumin accords protection against acute hypobaric hypoxia induced lung injury in rats. J Physiol Biochem 2016;74:763–79.10.1007/s13105-016-0515-3Search in Google Scholar
19. Brown DA, Lynch JM, Armstrong CJ, Caruso NM, Ehlers LB, Johnson MS, et al. Susceptibility of the heart to ischaemia – reperfusion injury and exercise-induced cardioprotection are sex-dependent in the rat. J Physiol 2005;2:619–30.10.1113/jphysiol.2004.081323Search in Google Scholar
20. Fulton RM, Hutchinson EC, Jones AM. Ventricular weight in cardiac hypertrophy. Br Heart J 1952;14:413–20.10.1136/hrt.14.3.413Search in Google Scholar
21. Cathcart R, Schwiers E, Ames BN. Detection of picomole levels of hydroperoxides using a fluorescent dichlorofluorescein assay. Anal Biochem 1983;134:111–6.10.1016/S0076-6879(84)05047-3Search in Google Scholar
22. Utley HG, Bernheim F, Hochstein P. Effect of sulfhydryl reagents on peroxidation in microsomes. Arch Biochem Biophys 1967;118:29–32.10.1016/0003-9861(67)90273-1Search in Google Scholar
23. Nehra S, Bhardwaj V, Saraswat D. Amlodipine protects rat ventricular cardiomyoblast H9c2 from hypoxia-induced apoptosis and restores oxidative balance by Akt-1-dependent manner. J Cardiovasc Pharmacol 2014;64:375–84.10.1097/FJC.0000000000000130Search in Google Scholar PubMed
24. Sartori C, Allemann Y, Duplain H, Lepori M, Egli M, Lipp E, et al. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med 2002;346:1631–6.10.1056/NEJMoa013183Search in Google Scholar PubMed
25. Lee SY, Li MH, Shi LS, Chu H, Ho CW, Chang TC. Rhodiola crenulata extract alleviates hypoxic pulmonary edema in rats. Evid Based Complement Alternat Med 2013;2013:1–9.10.1155/2013/718739Search in Google Scholar
26. Ma HP, Fan PC, Jing LL, Yao J, He XR, Yang Y, et al. Anti-hypoxic activity at simulated high altitude was isolated in petroleum ether extract of saussurea involucrata. J Ethnopharmacol 2011;137:1510–5.10.1016/j.jep.2011.08.037Search in Google Scholar PubMed
27. Burelle Y, Wambolt RB, Grist M, Parsons HL, Chow JC, Antler C, et al. Regular exercise is associated with a protective metabolic phenotype in the rat heart. Am J Physiol Heart Circ Physiol 2004;287:1055–63.10.1152/ajpheart.00925.2003Search in Google Scholar PubMed
28. Kemi OJ, Wisloff U. High-intensity aerobic exercise training improves the heart in health and disease. J Cardiopulm Rehabil Prev 2010;30:2–11.10.1097/HCR.0b013e3181c56b89Search in Google Scholar PubMed
29. Boccatonda A, Tripaldi R, Davi G, Santilli F. Oxidative stress modulation through habitual physical activity. Curr Pharm Des 2016;22:3648–80.10.2174/1381612822666160413123806Search in Google Scholar PubMed
30. Tabet JY, Meurin P, Driss AB, Weber H, Renaud N, Grosdemouge A, et al. Benefits of exercise training in chronic heart failure. Arch Cardiovasc Dis 2009;102:721–30.10.1016/j.acvd.2009.05.011Search in Google Scholar PubMed
31. Maxwell SR, Lip GY. Free radicals and antioxidants in cardiovascular disease. Br J Clin Pharmacol 1997;44:307–17.10.1046/j.1365-2125.1997.t01-1-00594.xSearch in Google Scholar PubMed PubMed Central
32. Robbins D, Zhao Y. Oxidative stress induced by MnSOD-p53 interaction: pro- or anti-tumorigenic? J Signal Transduct 2012;2012:1–13. Article ID 101465.10.1155/2012/101465Search in Google Scholar PubMed PubMed Central
33. Yamashita N, Nishida M, Hoshida S, Kuzuya T, Hori M, Taniguchi N. Induction of manganese superoxide dismutase in rat cardiac myocytes increases tolerance to hypoxia 24 hours after preconditioning. J Clin Invest 1994;94:2193–9.10.1172/JCI117580Search in Google Scholar
34. Elmedal B, de Dam MY, Mulvany MJ, Simonsen U. The superoxide dismutase mimetic, tempol, blunts right ventricular hypertrophy in chronic hypoxic rats. Br J Pharmacol 2004;141:105–13.10.1038/sj.bjp.0705580Search in Google Scholar
35. Rosenblatt-Velin N, Montessuit C, Papageorgiou I, Terrand J, Lerch R. Postinfarction heart failure in rats is associated with upregulation of GLUT-1 and downregulation of genes of fatty acid metabolism. Cardiovasc Res 2001;52:407–16.10.1016/S0008-6363(01)00393-5Search in Google Scholar
36. Beauloye C, Bertrand L, Horman S, Hue L. AMPK activation, a preventive therapeutic target in the transition from cardiac injury to heart failure. Cardiovasc Res 2011;90:224–33.10.1093/cvr/cvr034Search in Google Scholar PubMed
37. Hardie DG, Sakamoto K. AMPK: a key sensor of fuel and energy status in skeletal muscle. Physiology (Bethesda) 2006;21:48–60.10.1152/physiol.00044.2005Search in Google Scholar PubMed
38. Adams JE, Bodor GS, Davila-Roman VG, Delmez JA, Apple FS, Ladenson JH, et al. Cardiac troponin I. A marker with high specificity for cardiac injury. Circulation 1993;88:101–6.10.1161/01.CIR.88.1.101Search in Google Scholar PubMed
39. Kociol RD, Pang PS, Gheorghiade M, Fonarow GC, O’Connor CM, Felker GM. Troponin elevation in heart failure: prevalence, mechanisms, and clinical implications. J Am Coll Cardiol 2010;56:1071–8.10.1016/j.jacc.2010.06.016Search in Google Scholar PubMed
40. Downing J, Balady GJ. The role of exercise training in heart failure. J Am Coll Cardiol 2011;58:561–9.10.1016/j.jacc.2011.04.020Search in Google Scholar PubMed
41. Laughlin MH, Oltman CL, Bowles DK. Exercise training-induced adaptations in the coronary circulation. Med Sci Sports Exerc 1998;30:352–60.10.1097/00005768-199803000-00004Search in Google Scholar PubMed
42. Huonker M, Halle M, Keul J. Structural and functional adaptations of the cardiovascular system by training. Int J Sports Med 1996;17:164–72.10.1055/s-2007-972919Search in Google Scholar PubMed
43. Griendling KK, Fitzgerald GA. Oxidative stress and cardiovascular injury. Circulation 2003;108:2034–40.10.1161/01.CIR.0000093661.90582.c4Search in Google Scholar PubMed
©2017 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Review
- Natural product for the treatment of Alzheimer’s disease
- Behavior and Neuroprotection
- Evidence for the involvement of the GABA-ergic pathway in the anticonvulsant activity of the roots bark aqueous extract of Anthocleista djalonensis A. Chev. (Loganiaceae)
- Cardiovascular Function
- Cutaneous temperature sensitivity alteration in subjects with chronic stroke sequelae – pharmacological perspectives
- Combinatorial therapy of exercise-preconditioning and nanocurcumin formulation supplementation improves cardiac adaptation under hypobaric hypoxia
- Oxidative Stress
- Phellinus rimosus improves mitochondrial energy status and attenuates nephrotoxicity in diabetic rats
- Hepatoprotective effects of Vaccinium arctostaphylos against CCl4-induced acute liver injury in rats
- The impact of vitamin C on the relationship among inflammation, lipid peroxidation and platelet activation during analgesic nephropathy in rats
- Phytotherapy
- Antidiarrheal and antinociceptive activities of ethanol extract and its chloroform and pet ether fraction of Phrynium imbricatum (Roxb.) leaves in mice
- Amelioration of hyperglycemia and associated metabolic abnormalities by a combination of fenugreek (Trigonella foenum-graecum) seeds and onion (Allium cepa) in experimental diabetes
- An ethanolic extract of Desmodium adscendens exhibits antipsychotic-like activity in mice
Articles in the same Issue
- Frontmatter
- Review
- Natural product for the treatment of Alzheimer’s disease
- Behavior and Neuroprotection
- Evidence for the involvement of the GABA-ergic pathway in the anticonvulsant activity of the roots bark aqueous extract of Anthocleista djalonensis A. Chev. (Loganiaceae)
- Cardiovascular Function
- Cutaneous temperature sensitivity alteration in subjects with chronic stroke sequelae – pharmacological perspectives
- Combinatorial therapy of exercise-preconditioning and nanocurcumin formulation supplementation improves cardiac adaptation under hypobaric hypoxia
- Oxidative Stress
- Phellinus rimosus improves mitochondrial energy status and attenuates nephrotoxicity in diabetic rats
- Hepatoprotective effects of Vaccinium arctostaphylos against CCl4-induced acute liver injury in rats
- The impact of vitamin C on the relationship among inflammation, lipid peroxidation and platelet activation during analgesic nephropathy in rats
- Phytotherapy
- Antidiarrheal and antinociceptive activities of ethanol extract and its chloroform and pet ether fraction of Phrynium imbricatum (Roxb.) leaves in mice
- Amelioration of hyperglycemia and associated metabolic abnormalities by a combination of fenugreek (Trigonella foenum-graecum) seeds and onion (Allium cepa) in experimental diabetes
- An ethanolic extract of Desmodium adscendens exhibits antipsychotic-like activity in mice
