title: Targeted deletion of Tsc1 causes fatal cardiomyocyte hyperplasia independently of afterload.
abstract: Despite high expression levels, the role of Tsc1 in cardiovascular tissue is ill defined. We launched this study to examine the role of Tsc1 in cardiac physiology and pathology. Mice in which Tsc1 was deleted in cardiac tissue and vascular smooth muscle (Tsc1c/cSM22cre(+/-)), developed progressive cardiomegaly and hypertension and died early. Hearts of Tsc1c/cSM22cre(+/-) mice displayed a progressive increase in cardiomyocyte number, and to a lesser extent, size between the ages of 1 and 6 weeks. In addition, compared to control hearts, proliferation markers (phospho-histone 3 and PCNA) were elevated in Tsc1c/cSM22cre(+/-) cardiomyocytes at 0-4 weeks, suggesting that cardiomyocyte proliferation was the predominant mechanism underlying cardiomegaly in Tsc1c/cSM22cre(+/-) mice. To examine the contribution of Tsc1 deletion in peripheral vascular smooth muscle to the cardiac phenotype, Tsc1c/cSM22cre(+/-) mice were treated with the antihypertensive, hydralazine. Prevention of hypertension had no effect on survival, cardiac size, or cardiomyocyte number in these mice. We furthermore generated mice in which Tsc1 was deleted only in vascular smooth muscle but not in cardiac tissue (Tsc1c/cSMAcre-ER(T2+/-)). The Tsc1c/cSMAcre-ER(T2+/-) mice also developed hypertension. However, their survival was normal and no cardiac abnormalities were observed. Our results suggest that loss of Tsc1 in the heart causes cardiomegaly, which is driven by increased cardiomyocyte proliferation that also appears to confer relative resistance to afterload reduction. These findings support a critical role for the Tsc1 gene as gatekeeper in the protection against uncontrolled cardiac growth.
authors.affiliation: Pulmonary, Critical Care & Sleep Division, Department of Medicine, Tupper Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA. Electronic address: ukayyali@tuftsmedicalcenter.org.
authors.forename: Usamah S
authors.initials: US
authors.lastname: Kayyali
authors.affiliation: Pulmonary, Critical Care & Sleep Division, Department of Medicine, Tupper Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Larsen
authors.affiliation: Pulmonary, Critical Care & Sleep Division, Department of Medicine, Tupper Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bashiruddin
authors.affiliation: Divison of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Lewandowski
authors.affiliation: Divison of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Chinmay M
authors.initials: CM
authors.lastname: Trivedi
authors.affiliation: Pulmonary, Critical Care & Sleep Division, Department of Medicine, Tupper Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Rod R
authors.initials: RR
authors.lastname: Warburton
authors.affiliation: Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02111, USA.
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Parkhitko
authors.affiliation: Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02111, USA.
authors.forename: Tasha A
authors.initials: TA
authors.lastname: Morrison
authors.affiliation: Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02111, USA.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Henske
authors.affiliation: Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02111, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Chekaluk
authors.affiliation: Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02111, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.affiliation: Pulmonary, Critical Care & Sleep Division, Department of Medicine, Tupper Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Geraldine A
authors.initials: GA
authors.lastname: Finlay
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics*; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000502:physiology; D006965:Hyperplasia / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D060885:Multiplex Polymerase Chain Reaction; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins
keywords: Cardiac hyperplasia; Cardiomegaly; Cardiomyocyte proliferation; Hamartin; Smooth muscle cell; Tsc1