Enhanced Hypertrophy in Ob/ob Mice Due to an Impairment in Expression of Atrial Natriuretic Peptide

Overview

Journal Vascul Pharmacol

Specialties Cardiology & Vascular Diseases
Pharmacology

Date 2009 Jun 30

PMID 19560554

Citations 9

Authors

Eduardo Mascareno

Daniel Beckles

Manya Dhar-Mascareno

M A Q Siddiqui

Affiliations

Soon will be listed here.

Abstract

Rationale: We investigated the molecular mechanism(s) that play a role in leptin signaling during the development of left ventricular hypertrophy (LVH) due to pressure overload. To this end, ob/ob leptin deficient and C57BL/6J control mice were subjected transverse aortic constriction (TAC).

Methods: Control sham C57BL/6J and ob/ob mice, along with C57BL/6J and ob/ob leptin deficient mice were subjected transverse aortic constriction (TAC) for 15 days and then evaluated for morphological, physiological, and molecular changes associated with pressure overload hypertrophy.

Results: Evaluation by echocardiography revealed a significant increase in left ventricular mass (LVmass) and wall thickness in ob/ob mice subjected to transverse aortic constriction (TAC) as compared to C57BL/6J. Analysis of the expression of molecular markers of LVH, such as atrial natriuretic peptide (ANP), revealed a blunted increase in the level of ANP in ob/ob mice as compared to C57BL/6J mice. We observed that leptin plays a role in modulating the transcriptional activity of the promoter of the ANP gene. Leptin acts by regulating NFATc4, a member of the nuclear factor activated T cell (NFAT) family of transcription factors in cardiomyocytes. Our in vivo studies revealed that ob/ob mice subjected to TAC failed to activate the NFATc4 in the heart, however, intraperitoneal injection of leptin in ob/ob mice restored the NFATc4 DNA-binding activity and induced expression of the ANP gene.

Conclusion: This study establishes the role of leptin as an anti-hypertrophic agent during pressure overload hypertrophy, and suggests that a key molecular event is the leptin mediated activation of NFATc4 that regulates the transcriptional activation of the ANP gene promoter.

Citing Articles

Cardiac hypertrophy with obesity is augmented after pregnancy in C57BL/6 mice.

Che C, Dudick K, Shoemaker R Biol Sex Differ. 2019; 10(1):59.

PMID: 31842996 PMC: 6916003. DOI: 10.1186/s13293-019-0269-z.

Acute effects of insulin on circulating natriuretic peptide levels in humans.

Bachmann K, Deger S, Alsouqi A, Huang S, Xu M, Ferguson J PLoS One. 2018; 13(5):e0196869.

PMID: 29758041 PMC: 5951576. DOI: 10.1371/journal.pone.0196869.

Longitudinal micro-ultrasound assessment of the ob/ob mouse model: evaluation of cardiovascular, renal and hepatic parameters.

Di Lascio N, Kusmic C, Stea F, Lenzarini F, Barsanti C, Leloup A Int J Obes (Lond). 2017; 42(3):518-524.

PMID: 28883542 DOI: 10.1038/ijo.2017.219.

Beneficial effects of leptin treatment in a setting of cardiac dysfunction induced by transverse aortic constriction in mouse.

Gomez-Hurtado N, Dominguez-Rodriguez A, Mateo P, Fernandez-Velasco M, Val-Blasco A, Aizpun R J Physiol. 2017; 595(13):4227-4243.

PMID: 28374413 PMC: 5491865. DOI: 10.1113/JP274030.

The effects of exercise training and caloric restriction on the cardiac oxytocin natriuretic peptide system in the diabetic mouse.

Broderick T, Jankowski M, Gutkowska J Diabetes Metab Syndr Obes. 2017; 10:27-36.

PMID: 28138261 PMC: 5238809. DOI: 10.2147/DMSO.S115453.

References

Temsah R, Nemer M . GATA factors and transcriptional regulation of cardiac natriuretic peptide genes. Regul Pept. 2005; 128(3):177-85. DOI: 10.1016/j.regpep.2004.12.026. View

Rajapurohitam V, Gan X, Kirshenbaum L, Karmazyn M . The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes. Circ Res. 2003; 93(4):277-9. DOI: 10.1161/01.RES.0000089255.37804.72. View

Perego L, Pizzocri P, Corradi D, Maisano F, Paganelli M, Fiorina P . Circulating leptin correlates with left ventricular mass in morbid (grade III) obesity before and after weight loss induced by bariatric surgery: a potential role for leptin in mediating human left ventricular hypertrophy. J Clin Endocrinol Metab. 2005; 90(7):4087-93. DOI: 10.1210/jc.2004-1963. View

Clerk A, Cullingford T, Fuller S, Giraldo A, Markou T, Pikkarainen S . Signaling pathways mediating cardiac myocyte gene expression in physiological and stress responses. J Cell Physiol. 2007; 212(2):311-22. DOI: 10.1002/jcp.21094. View

Wang D, Oparil S, Feng J, Li P, Perry G, Chen L . Effects of pressure overload on extracellular matrix expression in the heart of the atrial natriuretic peptide-null mouse. Hypertension. 2003; 42(1):88-95. DOI: 10.1161/01.HYP.0000074905.22908.A6. View

Pladevall M, Williams K, Guyer H, Sadurni J, Falces C, Ribes A . The association between leptin and left ventricular hypertrophy: a population-based cross-sectional study. J Hypertens. 2003; 21(8):1467-73. DOI: 10.1097/00004872-200308000-00009. View

London B . Natriuretic peptides and cardiac hypertrophy. J Am Coll Cardiol. 2006; 48(3):506-7. DOI: 10.1016/j.jacc.2006.05.020. View

Feng J, Perry G, Mori T, Hayashi T, Oparil S, Chen Y . Pressure-independent enhancement of cardiac hypertrophy in atrial natriuretic peptide-deficient mice. Clin Exp Pharmacol Physiol. 2003; 30(5-6):343-9. DOI: 10.1046/j.1440-1681.2003.03836.x. View

Nishikimi T, Maeda N, Matsuoka H . The role of natriuretic peptides in cardioprotection. Cardiovasc Res. 2005; 69(2):318-28. DOI: 10.1016/j.cardiores.2005.10.001. View

10.

Swynghedauw B . Phenotypic plasticity of adult myocardium: molecular mechanisms. J Exp Biol. 2006; 209(Pt 12):2320-7. DOI: 10.1242/jeb.02084. View

11.

Abe Y, Ono K, Kawamura T, Wada H, Kita T, Shimatsu A . Leptin induces elongation of cardiac myocytes and causes eccentric left ventricular dilatation with compensation. Am J Physiol Heart Circ Physiol. 2007; 292(5):H2387-96. DOI: 10.1152/ajpheart.00579.2006. View

12.

Barouch L, Berkowitz D, Harrison R, ODonnell C, Hare J . Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation. 2003; 108(6):754-9. DOI: 10.1161/01.CIR.0000083716.82622.FD. View

13.

Wilkins B, Dai Y, Bueno O, Parsons S, Xu J, Plank D . Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ Res. 2003; 94(1):110-8. DOI: 10.1161/01.RES.0000109415.17511.18. View

14.

Trivedi P, Yang R, Barouch L . Decreased p110alpha catalytic activity accompanies increased myocyte apoptosis and cardiac hypertrophy in leptin deficient ob/ob mice. Cell Cycle. 2008; 7(5):560-5. DOI: 10.4161/cc.7.5.5529. View

15.

Minhas K, Khan S, Raju S, Phan A, Gonzalez D, Skaf M . Leptin repletion restores depressed {beta}-adrenergic contractility in ob/ob mice independently of cardiac hypertrophy. J Physiol. 2005; 565(Pt 2):463-74. PMC: 1464532. DOI: 10.1113/jphysiol.2005.084566. View

16.

McGaffin K, Sun C, Rager J, Romano L, Zou B, Mathier M . Leptin signalling reduces the severity of cardiac dysfunction and remodelling after chronic ischaemic injury. Cardiovasc Res. 2007; 77(1):54-63. DOI: 10.1093/cvr/cvm023. View

17.

Oliver P, Fox J, Kim R, Rockman H, Kim H, Reddick R . Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc Natl Acad Sci U S A. 1998; 94(26):14730-5. PMC: 25105. DOI: 10.1073/pnas.94.26.14730. View

18.

Houweling A, van Borren M, Moorman A, Christoffels V . Expression and regulation of the atrial natriuretic factor encoding gene Nppa during development and disease. Cardiovasc Res. 2005; 67(4):583-93. DOI: 10.1016/j.cardiores.2005.06.013. View

19.

Zang M, Li Y, Xue L, Jia H, Jing H . Cooperative activation of atrial naturetic peptide promoter by dHAND and MEF2C. J Cell Biochem. 2004; 93(6):1255-66. DOI: 10.1002/jcb.20225. View

20.

Christoffersen C, Bollano E, Lindegaard M, Bartels E, Goetze J, Andersen C . Cardiac lipid accumulation associated with diastolic dysfunction in obese mice. Endocrinology. 2003; 144(8):3483-90. DOI: 10.1210/en.2003-0242. View