Cholesterol depletion enhances adrenergic signaling in cardiac myocytes.
Cardiac myocytes endogenously express α and β adrenergic receptors, prototypes of the G-protein coupled receptor superfamily. Depending upon the dose of norepinephrine (agonist) exposure, hypertrophy and apoptosis are initiated by differential induction of two discrete constituents of the transcription factor AP-1, i.e., FosB and Fra-1. We explored differential adrenergic signaling as a paradigm for understanding how cholesterol dictates cells to choose hypertrophy or apoptosis. For this, we used fosB and fra-1 promoter-reporter constructs for monitoring adrenergic signaling. We show that cholesterol depletion enhances norepinephrine-mediated signaling in cardiac myocytes. Importantly, this increased signaling is reduced to original level upon cholesterol replenishment. We used specific ligands for α and β adrenergic receptors and show that the enhanced signaling upon cholesterol depletion is a combined effect of both α and β adrenergic receptors. These results constitute the first report demonstrating the effect of cholesterol on adrenergic signaling using a direct end-point gene expression.
Paila
Yamuna Devi
YD
Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research Uppal Road, Hyderabad 500 007, India.
Jindal
Ekta
E
Goswami
Shyamal K
SK
Chattopadhyay
Amitabha
A
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008957:Models, Genetic; D032383:Myocytes, Cardiac / Q000166:cytology*; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D051381:Rats; D011941:Receptors, Adrenergic / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D000099169:Fos-Related Antigen 1
D002784:Cholesterol; D008024:Ligands; D008156:Luciferases; D016760:Proto-Oncogene Proteins c-fos; D011941:Receptors, Adrenergic; D000099169:Fos-Related Antigen 1; C483820:Fosb protein, rat