Estrogen receptor beta signals to inhibition of cardiac fibrosis.
Cardiac fibrosis evolves from the cardiac hypertrophic state. In this respect, estrogen and estrogen receptor beta (ERβ) inhibit the effects of cardiac hypertrophic peptides that also stimulate fibrosis. Here we determine details of the anti-fibrotic functions of ERβ. In acutely isolated rat cardiac fibroblasts. E2 or a specific ERβ agonist (βLGND2) blocked angiotensin II (AngII) signaling to fibrosis. This resulted from ERβ activating protein kinase A and AMP kinase, inhibiting both AngII de-phosphorylation of RhoA and the resulting stimulation of Rho kinase. Inhibition of Rho kinase from ERβ signaling resulted in marked decrease of TGFβ expression, connective tissue growth factor production and function, matrix metalloproteinases 2 and 9 expression and activity, and the conversion of fibroblasts to myofibroblasts. Production of collagens I and III were also significantly decreased. Several important aspects were corroborated in-vivo from βLGND2-treated mice that underwent AngII-induced cardiac hypertrophy. Thus, ERβ in cardiac fibroblasts prevents key aspects of cardiac fibrosis development.
Division of Endocrinology, Veterans Affairs Medical Center, Long Beach, Long Beach, CA 90822, United States.
Ali
A
Pedram
Division of Endocrinology, Veterans Affairs Medical Center, Long Beach, Long Beach, CA 90822, United States.
Mahnaz
M
Razandi
Department of Medicine, University of Tennessee, Memphis, TE, 38163, United States.
Ramesh
R
Narayanan
Division of Endocrinology, Veterans Affairs Medical Center, Long Beach, Long Beach, CA 90822, United States; Departments of Medicine and Biochemistry, University of California, Irvine, Irvine, CA 92717, United States. Electronic address: ellis.levin@va.gov.
Ellis R
ER
Levin
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D004195:Disease Models, Animal; D047629:Estrogen Receptor beta / Q000819:agonists / Q000378:metabolism*; D005355:Fibrosis; D008297:Male; D051379:Mice; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
D024042:Collagen Type I; D024061:Collagen Type III; D047629:Estrogen Receptor beta; D000804:Angiotensin II; D055372:AMP-Activated Protein Kinases
AMP-Activated kinase (AMPK); Angiotensin II; Estrogen receptor; Fibrosis