Enhanced hypertrophy in ob/ob mice due to an impairment in expression of atrial natriuretic peptide

Autor: Daniel L. Beckles, Manya Dhar-Mascareno, Eduardo Mascareno, M.A.Q. Siddiqui
Rok vydání: 2009
Předmět:
Genetic Markers
Leptin
Male
Chromatin Immunoprecipitation
medicine.medical_specialty
Time Factors
Physiology
Heart Ventricles
Calcineurin Inhibitors
Gene Expression
Mice
Obese
Electrophoretic Mobility Shift Assay
Constriction
Pathologic
Left ventricular hypertrophy
Article
Cell Line
Muscle hypertrophy
Mice
Atrial natriuretic peptide
Internal medicine
medicine
Animals
Myocyte
Myocytes
Cardiac
Obesity
Promoter Regions
Genetic
Ventricular remodeling
Aorta
Pharmacology
Pressure overload
Analysis of Variance
NFATC Transcription Factors
Ventricular Remodeling
Chemistry
NFAT
medicine.disease
Immunohistochemistry
Rats
DNA-Binding Proteins
Mice
Inbred C57BL
Protein Transport
Endocrinology
cardiovascular system
Molecular Medicine
Hypertrophy
Left Ventricular
Atrial Natriuretic Factor
hormones
hormone substitutes
and hormone antagonists
Zdroj: Vascular Pharmacology. 51:198-204
ISSN: 1537-1891
DOI: 10.1016/j.vph.2009.06.005
Popis: 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.
Databáze: OpenAIRE
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