Exercise training worsens cardiac performance in males but does not change ejection fraction and improves hypertrophy in females in a mouse model of metabolic syndrome.
Cardio-metabolic disease
Diastolic function
Endoplasmic reticulum stress
Endurance training
Heart failure
Hyperlipidemia
Left ventricular hypertrophy
Metabolic syndrome
Obesity
Sex-based differences
Journal
Biology of sex differences
ISSN: 2042-6410
Titre abrégé: Biol Sex Differ
Pays: England
ID NLM: 101548963
Informations de publication
Date de publication:
31 01 2022
31 01 2022
Historique:
received:
16
09
2021
accepted:
05
01
2022
entrez:
1
2
2022
pubmed:
2
2
2022
medline:
6
5
2022
Statut:
epublish
Résumé
Metabolic syndrome (MetS) refers to a cluster of co-existing cardio-metabolic risk factors, including visceral obesity, dyslipidemia, hyperglycemia with insulin resistance, and hypertension. As there is a close link between MetS and cardiovascular diseases, we aimed to investigate the sex-based differences in MetS-associated heart failure (HF) and cardiovascular response to regular exercise training (ET). High-fat diet-fed male and female APOB-100 transgenic (HFD/APOB-100, 3 months) mice were used as MetS models, and age- and sex-matched C57BL/6 wild-type mice on standard diet served as healthy controls (SD/WT). Both the SD/WT and HFD/APOB-100 mice were divided into sedentary and ET groups, the latter running on a treadmill (0.9 km/h) for 45 min 5 times per week for 7 months. At month 9, transthoracic echocardiography was performed to monitor cardiac function and morphology. At the termination of the experiment at month 10, blood was collected for serum low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol measurements and homeostatic assessment model for insulin resistance (HOMA-IR) calculation. Cardiomyocyte hypertrophy and fibrosis were assessed by histology. Left ventricular expressions of selected genes associated with metabolism, inflammation, and stress response were investigated by qPCR. Both HFD/APOB-100 males and females developed obesity and hypercholesterolemia; however, only males showed insulin resistance. ET did not change these metabolic parameters. HFD/APOB-100 males showed echocardiographic signs of mild HF with dilated ventricles and thinner walls, whereas females presented the beginning of left ventricular hypertrophy. In response to ET, SD/WT males developed increased left ventricular volumes, whereas females responded with physiologic hypertrophy. Exercise-trained HFD/APOB-100 males presented worsening HF with reduced ejection fraction; however, ET did not change the ejection fraction and reversed the echocardiographic signs of left ventricular hypertrophy in HFD/APOB-100 females. The left ventricular expression of the leptin receptor was higher in females than males in the SD/WT groups. Left ventricular expression levels of stress response-related genes were higher in the exercise-trained HFD/APOB-100 males and exercise-trained SD/WT females than exercise-trained SD/WT males. HFD/APOB-100 mice showed sex-specific cardiovascular responses to MetS and ET; however, left ventricular gene expressions were similar between the groups except for leptin receptor and several stress response-related genes.
Sections du résumé
BACKGROUND
Metabolic syndrome (MetS) refers to a cluster of co-existing cardio-metabolic risk factors, including visceral obesity, dyslipidemia, hyperglycemia with insulin resistance, and hypertension. As there is a close link between MetS and cardiovascular diseases, we aimed to investigate the sex-based differences in MetS-associated heart failure (HF) and cardiovascular response to regular exercise training (ET).
METHODS
High-fat diet-fed male and female APOB-100 transgenic (HFD/APOB-100, 3 months) mice were used as MetS models, and age- and sex-matched C57BL/6 wild-type mice on standard diet served as healthy controls (SD/WT). Both the SD/WT and HFD/APOB-100 mice were divided into sedentary and ET groups, the latter running on a treadmill (0.9 km/h) for 45 min 5 times per week for 7 months. At month 9, transthoracic echocardiography was performed to monitor cardiac function and morphology. At the termination of the experiment at month 10, blood was collected for serum low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol measurements and homeostatic assessment model for insulin resistance (HOMA-IR) calculation. Cardiomyocyte hypertrophy and fibrosis were assessed by histology. Left ventricular expressions of selected genes associated with metabolism, inflammation, and stress response were investigated by qPCR.
RESULTS
Both HFD/APOB-100 males and females developed obesity and hypercholesterolemia; however, only males showed insulin resistance. ET did not change these metabolic parameters. HFD/APOB-100 males showed echocardiographic signs of mild HF with dilated ventricles and thinner walls, whereas females presented the beginning of left ventricular hypertrophy. In response to ET, SD/WT males developed increased left ventricular volumes, whereas females responded with physiologic hypertrophy. Exercise-trained HFD/APOB-100 males presented worsening HF with reduced ejection fraction; however, ET did not change the ejection fraction and reversed the echocardiographic signs of left ventricular hypertrophy in HFD/APOB-100 females. The left ventricular expression of the leptin receptor was higher in females than males in the SD/WT groups. Left ventricular expression levels of stress response-related genes were higher in the exercise-trained HFD/APOB-100 males and exercise-trained SD/WT females than exercise-trained SD/WT males.
CONCLUSIONS
HFD/APOB-100 mice showed sex-specific cardiovascular responses to MetS and ET; however, left ventricular gene expressions were similar between the groups except for leptin receptor and several stress response-related genes.
Identifiants
pubmed: 35101146
doi: 10.1186/s13293-022-00414-6
pii: 10.1186/s13293-022-00414-6
pmc: PMC8805345
doi:
Substances chimiques
Apolipoprotein B-100
0
Receptors, Leptin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5Informations de copyright
© 2022. The Author(s).
Références
de Waard A-KM, Hollander M, Korevaar JC, Nielen MMJ, Carlsson AC, Lionis C, et al. Selective prevention of cardiometabolic diseases: activities and attitudes of general practitioners across Europe. Eur J Public Health. 2019;29:88–93. https://doi.org/10.1093/eurpub/cky112 .
doi: 10.1093/eurpub/cky112
Lusis AJ, Attie AD, Reue K. Metabolic syndrome: from epidemiology to systems biology. Nat Rev Genet. 2008;9:819–30. https://doi.org/10.1038/nrg2468 .
doi: 10.1038/nrg2468
Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384:766–81. https://doi.org/10.1016/S0140-6736(14)60460-8 .
doi: 10.1016/S0140-6736(14)60460-8
Razavi AC, Potts KS, Kelly TN, Bazzano LA. Sex, gut microbiome, and cardiovascular disease risk. Biol Sex Differ. 2019;10:29. https://doi.org/10.1186/s13293-019-0240-z .
doi: 10.1186/s13293-019-0240-z
Gerdts E, Regitz-Zagrosek V. Sex differences in cardiometabolic disorders. Nat Med. 2019;25:1657–66. https://doi.org/10.1038/s41591-019-0643-8 .
doi: 10.1038/s41591-019-0643-8
O’Neill S, O’Driscoll L. Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes Rev. 2015;16:1–12. https://doi.org/10.1111/obr.12229 .
doi: 10.1111/obr.12229
Tune JD, Goodwill AG, Sassoon DJ, Mather KJ. Cardiovascular consequences of metabolic syndrome. Transl Res. 2017;183:57–70. https://doi.org/10.1016/j.trsl.2017.01.001 .
doi: 10.1016/j.trsl.2017.01.001
Tóth ME, Dukay B, Péter M, Balogh G, Szűcs G, Zvara Á, et al. Male and female animals respond differently to high-fat diet and regular exercise training in a mouse model of hyperlipidemia. Int J Mol Sci. 2021. https://doi.org/10.3390/ijms22084198 .
doi: 10.3390/ijms22084198
Kaabia Z, Poirier J, Moughaizel M, Aguesse A, Billon-Crossouard S, Fall F, et al. Plasma lipidomic analysis reveals strong similarities between lipid fingerprints in human, hamster and mouse compared to other animal species. Sci Rep. 2018;8:15893. https://doi.org/10.1038/s41598-018-34329-3 .
doi: 10.1038/s41598-018-34329-3
Callow MJ, Stoltzfus LJ, Lawn RM, Rubin EM. Expression of human apolipoprotein B and assembly of lipoprotein(a) in transgenic mice. Proc Natl Acad Sci U S A. 1994;91:2130–4. https://doi.org/10.1073/pnas.91.6.2130 .
doi: 10.1073/pnas.91.6.2130
Purcell-Huynh DA, Farese RV, Johnson DF, Flynn LM, Pierotti V, Newland DL, et al. Transgenic mice expressing high levels of human apolipoprotein B develop severe atherosclerotic lesions in response to a high-fat diet. J Clin Invest. 1995;95:2246–57. https://doi.org/10.1172/JCI117915 .
doi: 10.1172/JCI117915
Csont T, Bereczki E, Bencsik P, Fodor G, Görbe A, Zvara A, et al. Hypercholesterolemia increases myocardial oxidative and nitrosative stress thereby leading to cardiac dysfunction in apoB-100 transgenic mice. Cardiovasc Res. 2007;76:100–9. https://doi.org/10.1016/j.cardiores.2007.06.006 .
doi: 10.1016/j.cardiores.2007.06.006
Tóth ME, Dukay B, Hoyk Z, Sántha M. Cerebrovascular changes and neurodegeneration related to hyperlipidemia: characteristics of the human ApoB-100 transgenic mice. Curr Pharm Des. 2020;26:1486–94. https://doi.org/10.2174/1381612826666200218101818 .
doi: 10.2174/1381612826666200218101818
Lénárt N, Szegedi V, Juhász G, Kasztner A, Horváth J, Bereczki E, et al. Increased tau phosphorylation and impaired presynaptic function in hypertriglyceridemic ApoB-100 transgenic mice. PLoS ONE. 2012;7: e46007. https://doi.org/10.1371/journal.pone.0046007 .
doi: 10.1371/journal.pone.0046007
Ventura-Clapier R, Dworatzek E, Seeland U, Kararigas G, Arnal J-F, Brunelleschi S, et al. Sex in basic research: concepts in the cardiovascular field. Cardiovasc Res. 2017;113:711–24. https://doi.org/10.1093/cvr/cvx066 .
doi: 10.1093/cvr/cvx066
Lam CSP, Arnott C, Beale AL, Chandramouli C, Hilfiker-Kleiner D, Kaye DM, et al. Sex differences in heart failure. Eur Heart J. 2019;40:3859–3868c. https://doi.org/10.1093/eurheartj/ehz835 .
doi: 10.1093/eurheartj/ehz835
Murphy E, Amanakis G, Fillmore N, Parks RJ, Sun J. Sex differences in metabolic cardiomyopathy. Cardiovasc Res. 2017;113:370–7. https://doi.org/10.1093/cvr/cvx008 .
doi: 10.1093/cvr/cvx008
Regitz-Zagrosek V, Lehmkuhl E, Mahmoodzadeh S. Gender aspects of the role of the metabolic syndrome as a risk factor for cardiovascular disease. Gend Med. 2007;4:S162–77. https://doi.org/10.1016/s1550-8579(07)80056-8 .
doi: 10.1016/s1550-8579(07)80056-8
Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;74:1376–414. https://doi.org/10.1016/j.jacc.2019.03.009 .
doi: 10.1016/j.jacc.2019.03.009
Serrano-Ferrer J, Crendal E, Walther G, Vinet A, Dutheil F, Naughton G, et al. Effects of lifestyle intervention on left ventricular regional myocardial function in metabolic syndrome patients from the RESOLVE randomized trial. Metabolism. 2016;65:1350–60. https://doi.org/10.1016/j.metabol.2016.05.006 .
doi: 10.1016/j.metabol.2016.05.006
Teixeira-Lemos E, Nunes S, Teixeira F, Reis F. Regular physical exercise training assists in preventing type 2 diabetes development: focus on its antioxidant and anti-inflammatory properties. Cardiovasc Diabetol. 2011;10:12. https://doi.org/10.1186/1475-2840-10-12 .
doi: 10.1186/1475-2840-10-12
Paley CA, Johnson MI. Abdominal obesity and metabolic syndrome: exercise as medicine? BMC Sports Sci Med Rehabil. 2018;10:7. https://doi.org/10.1186/s13102-018-0097-1 .
doi: 10.1186/s13102-018-0097-1
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–200. https://doi.org/10.1093/eurheartj/ehw128 .
doi: 10.1093/eurheartj/ehw128
Eisenberg E, Di Palo KE, Piña IL. Sex differences in heart failure. Clin Cardiol. 2018;41:211–6. https://doi.org/10.1002/clc.22917 .
doi: 10.1002/clc.22917
Bjelik A, Bereczki E, Gonda S, Juhász A, Rimanóczy A, Zana M, et al. Human apoB overexpression and a high-cholesterol diet differently modify the brain APP metabolism in the transgenic mouse model of atherosclerosis. Neurochem Int. 2006;49:393–400. https://doi.org/10.1016/j.neuint.2006.01.026 .
doi: 10.1016/j.neuint.2006.01.026
Bereczki E, Bernát G, Csont T, Ferdinandy P, Scheich H, Sántha M. Overexpression of human apolipoprotein B-100 induces severe neurodegeneration in transgenic mice. J Proteome Res. 2008;7:2246–52. https://doi.org/10.1021/pr7006329 .
doi: 10.1021/pr7006329
Sallo FB, Bereczki E, Csont T, Luthert PJ, Munro P, Ferdinandy P, et al. Bruch’s membrane changes in transgenic mice overexpressing the human biglycan and apolipoprotein b-100 genes. Exp Eye Res. 2009;89:178–86. https://doi.org/10.1016/j.exer.2009.03.006 .
doi: 10.1016/j.exer.2009.03.006
Szűcs G, Sója A, Péter M, Sárközy M, Bruszel B, Siska A, et al. Prediabetes induced by fructose-enriched diet influences cardiac lipidome and proteome and leads to deterioration of cardiac function prior to the development of excessive oxidative stress and cell damage. Oxid Med Cell Longev. 2019;2019:3218275. https://doi.org/10.1155/2019/3218275 .
doi: 10.1155/2019/3218275
Sárközy M, Szűcs G, Fekete V, Pipicz M, Éder K, Gáspár R, et al. Transcriptomic alterations in the heart of non-obese type 2 diabetic Goto-Kakizaki rats. Cardiovasc Diabetol. 2016;15:110. https://doi.org/10.1186/s12933-016-0424-3 .
doi: 10.1186/s12933-016-0424-3
Sárközy M, Zvara A, Gyémánt N, Fekete V, Kocsis GF, Pipis J, et al. Metabolic syndrome influences cardiac gene expression pattern at the transcript level in male ZDF rats. Cardiovasc Diabetol. 2013;12:16. https://doi.org/10.1186/1475-2840-12-16 .
doi: 10.1186/1475-2840-12-16
Barr ELM, Cameron AJ, Balkau B, Zimmet PZ, Welborn TA, Tonkin AM, Shaw JE. HOMA insulin sensitivity index and the risk of all-cause mortality and cardiovascular disease events in the general population: the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) study. Diabetologia. 2010;53:79–88. https://doi.org/10.1007/s00125-009-1588-0 .
doi: 10.1007/s00125-009-1588-0
Kovács ZZA, Szűcs G, Freiwan M, Kovács MG, Márványkövi FM, Dinh H, et al. Comparison of the antiremodeling effects of losartan and mirabegron in a rat model of uremic cardiomyopathy. Sci Rep. 2021. https://doi.org/10.1038/s41598-021-96815-5 .
doi: 10.1038/s41598-021-96815-5
Salton CJ, Chuang ML, O’Donnell CJ, Kupka MJ, Larson MG, Kissinger KV, et al. Gender differences and normal left ventricular anatomy in an adult population free of hypertension. J Am Coll Cardiol. 2002;39:1055–60. https://doi.org/10.1016/s0735-1097(02)01712-6 .
doi: 10.1016/s0735-1097(02)01712-6
Oneglia A, Nelson MD, Merz CNB. Sex differences in cardiovascular aging and heart failure. Curr Heart Fail Rep. 2020;17:409–23. https://doi.org/10.1007/s11897-020-00487-7 .
doi: 10.1007/s11897-020-00487-7
Hayward C. The roles of gender, the menopause and hormone replacement on cardiovascular function. Cardiovasc Res. 2000;46:28–49. https://doi.org/10.1016/s0008-6363(00)00005-5 .
doi: 10.1016/s0008-6363(00)00005-5
Barrett-Connor E. Sex differences in coronary heart disease. Why are women so superior? The 1995 Ancel Keys Lecture. Circulation. 1997;1997(95):252–64. https://doi.org/10.1161/01.cir.95.1.252 .
doi: 10.1161/01.cir.95.1.252
Nakamura M, Sadoshima J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol. 2018;15:387–407. https://doi.org/10.1038/s41569-018-0007-y .
doi: 10.1038/s41569-018-0007-y
Swank AM, Horton J, Fleg JL, Fonarow GC, Keteyian S, Goldberg L, et al. Modest increase in peak VO2 is related to better clinical outcomes in chronic heart failure patients: results from heart failure and a controlled trial to investigate outcomes of exercise training. Circ Heart Fail. 2012;5:579–85. https://doi.org/10.1161/CIRCHEARTFAILURE.111.965186 .
doi: 10.1161/CIRCHEARTFAILURE.111.965186
Nystoriak MA, Bhatnagar A. Cardiovascular effects and benefits of exercise. Front Cardiovasc Med. 2018;5:135. https://doi.org/10.3389/fcvm.2018.00135 .
doi: 10.3389/fcvm.2018.00135
Tian D, Meng J. Exercise for prevention and relief of cardiovascular disease: prognoses, mechanisms, and approaches. Oxid Med Cell Longev. 2019;2019:3756750. https://doi.org/10.1155/2019/3756750 .
doi: 10.1155/2019/3756750
McGaffin KR, Witham WG, Yester KA, Romano LC, O’Doherty RM, McTiernan CF, O’Donnell CP. Cardiac-specific leptin receptor deletion exacerbates ischaemic heart failure in mice. Cardiovasc Res. 2011;89:60–71. https://doi.org/10.1093/cvr/cvq288 .
doi: 10.1093/cvr/cvq288
Martínez-Martínez E, Jurado-López R, Cervantes-Escalera P, Cachofeiro V, Miana M. Leptin, a mediator of cardiac damage associated with obesity. Horm Mol Biol Clin Investig. 2014;18:3–14. https://doi.org/10.1515/hmbci-2013-0060 .
doi: 10.1515/hmbci-2013-0060
Poetsch MS, Strano A, Guan K. Role of leptin in cardiovascular diseases. Front Endocrinol (Lausanne). 2020;11:354. https://doi.org/10.3389/fendo.2020.00354 .
doi: 10.3389/fendo.2020.00354
Xu F-P, Chen M-S, Wang Y-Z, Yi Q, Lin S-B, Chen AF, Luo J-D. Leptin induces hypertrophy via endothelin-1-reactive oxygen species pathway in cultured neonatal rat cardiomyocytes. Circulation. 2004;110:1269–75. https://doi.org/10.1161/01.CIR.0000140766.52771.6D .
doi: 10.1161/01.CIR.0000140766.52771.6D
Hall ME, Harmancey R, Stec DE. Lean heart: role of leptin in cardiac hypertrophy and metabolism. World J Cardiol. 2015;7:511–24. https://doi.org/10.4330/wjc.v7.i9.511 .
doi: 10.4330/wjc.v7.i9.511
Aroor AR, Mandavia CH, Sowers JR. Insulin resistance and heart failure: molecular mechanisms. Heart Fail Clin. 2012;8:609–17. https://doi.org/10.1016/j.hfc.2012.06.005 .
doi: 10.1016/j.hfc.2012.06.005
Guo S. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. J Endocrinol. 2014;220:T1–23. https://doi.org/10.1530/JOE-13-0327 .
doi: 10.1530/JOE-13-0327
Qi Y, Xu Z, Zhu Q, Thomas C, Kumar R, Feng H, et al. Myocardial loss of IRS1 and IRS2 causes heart failure and is controlled by p38α MAPK during insulin resistance. Diabetes. 2013;62:3887–900. https://doi.org/10.2337/db13-0095 .
doi: 10.2337/db13-0095
Penke B, Bogár F, Crul T, Sántha M, Tóth ME, Vígh L. Heat shock proteins and autophagy pathways in neuroprotection: from molecular bases to pharmacological interventions. Int J Mol Sci. 2018. https://doi.org/10.3390/ijms19010325 .
doi: 10.3390/ijms19010325
Latchman D. Heat shock proteins and cardiac protection. Cardiovasc Res. 2001;51:637–46. https://doi.org/10.1016/S0008-6363(01)00354-6 .
doi: 10.1016/S0008-6363(01)00354-6
Tóth ME, Gombos I, Sántha M. Heat shock proteins and their role in human diseases. Acta Biologica Szegediensis. 2015;59(Suppl. 1):121–41.
Quindry JC, Hamilton KL, French JP, Lee Y, Murlasits Z, Tumer N, Powers SK. Exercise-induced HSP-72 elevation and cardioprotection against infarct and apoptosis. J Appl Physiol. 1985;2007(103):1056–62. https://doi.org/10.1152/japplphysiol.00263.2007 .
doi: 10.1152/japplphysiol.00263.2007
Hooper PL, Balogh G, Rivas E, Kavanagh K, Vigh L. The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes. Cell Stress Chaperones. 2014;19:447–64. https://doi.org/10.1007/s12192-014-0493-8 .
doi: 10.1007/s12192-014-0493-8
Csont T, Balogh G, Csonka C, Boros I, Horváth I, Vigh L, Ferdinandy P. Hyperlipidemia induced by high cholesterol diet inhibits heat shock response in rat hearts. Biochem Biophys Res Commun. 2002;290:1535–8. https://doi.org/10.1006/bbrc.2002.6377 .
doi: 10.1006/bbrc.2002.6377
Oslowski CM, Urano F. Measuring ER stress and the unfolded protein response using mammalian tissue culture system. Methods Enzymol. 2011;490:71–92. https://doi.org/10.1016/B978-0-12-385114-7.00004-0 .
doi: 10.1016/B978-0-12-385114-7.00004-0
Samali A, Fitzgerald U, Deegan S, Gupta S. Methods for monitoring endoplasmic reticulum stress and the unfolded protein response. Int J Cell Biol. 2010;2010: 830307. https://doi.org/10.1155/2010/830307 .
doi: 10.1155/2010/830307
Willis MS, Patterson C. Hold me tight: role of the heat shock protein family of chaperones in cardiac disease. Circulation. 2010;122:1740–51. https://doi.org/10.1161/CIRCULATIONAHA.110.942250 .
doi: 10.1161/CIRCULATIONAHA.110.942250
Banerjee I, Fuseler JW, Price RL, Borg TK, Baudino TA. Determination of cell types and numbers during cardiac development in the neonatal and adult rat and mouse. Am J Physiol Heart Circ Physiol. 2007;293:H1883–91. https://doi.org/10.1152/ajpheart.00514.2007 .
doi: 10.1152/ajpheart.00514.2007