title: p90 ribosomal S6 kinase 3 contributes to cardiac insufficiency in α-tropomyosin Glu180Gly transgenic mice.
abstract: Myocardial interstitial fibrosis is an important contributor to the development of heart failure. Type 3 p90 ribosomal S6 kinase (RSK3) was recently shown to be required for concentric myocyte hypertrophy under in vivo pathological conditions. However, the role of RSK family members in myocardial fibrosis remains uninvestigated. Transgenic expression of α-tropomyosin containing a Glu180Gly mutation (TM180) in mice of a mixed C57BL/6:FVB/N background induces a cardiomyopathy characterized by a small left ventricle, interstitial fibrosis, and diminished systolic and diastolic function. Using this mouse model, we now show that RSK3 is required for the induction of interstitial fibrosis in vivo. TM180 transgenic mice were crossed to RSK3 constitutive knockout (RSK3(-/-)) mice. Although RSK3 knockout did not affect myocyte growth, the decreased cardiac function and mild pulmonary edema associated with the TM180 transgene were attenuated by RSK3 knockout. The improved cardiac function was consistent with reduced interstitial fibrosis in the TM180;RSK3(-/-) mice as shown by histology and gene expression analysis, including the decreased expression of collagens. The specific inhibition of RSK3 should be considered as a potential novel therapeutic strategy for improving cardiac function and the prevention of sudden cardiac death in diseases in which interstitial fibrosis contributes to the development of heart failure.
authors.affiliation: Cardiac Signal Transduction and Cellular Biology Laboratory, Interdisciplinary Stem Cell Institute, Departments of Pediatrics and Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida; and.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Passariello
authors.forename: Marjorie
authors.initials: M
authors.lastname: Gayanilo
authors.forename: Michael D
authors.initials: MD
authors.lastname: Kritzer
authors.forename: Hrishikesh
authors.initials: H
authors.lastname: Thakur
authors.forename: Zoharit
authors.initials: Z
authors.lastname: Cozacov
authors.forename: Francesca
authors.initials: F
authors.lastname: Rusconi
authors.forename: David
authors.initials: D
authors.lastname: Wieczorek
authors.forename: Michael
authors.initials: M
authors.lastname: Sanders
authors.forename: Jinliang
authors.initials: J
authors.lastname: Li
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kapiloff
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D005355:Fibrosis; D005786:Gene Expression Regulation; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D011654:Pulmonary Edema / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013318:Stroke Volume; D014335:Tropomyosin / Q000235:genetics / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D016277:Ventricular Function, Left
chemical_list: D014335:Tropomyosin; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3
keywords: fibrosis; ribosomal S6 kinase; α-tropomyosin
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