title: Partial Liver Kinase B1 (LKB1) Deficiency Promotes Diastolic Dysfunction, De Novo Systolic Dysfunction, Apoptosis, and Mitochondrial Dysfunction With Dietary Metabolic Challenge.
abstract: BACKGROUND
  Myocardial hypertrophy and dysfunction are key features of metabolic heart disease due to dietary excess. Metabolic heart disease manifests primarily as diastolic dysfunction but may progress to systolic dysfunction, although the mechanism is poorly understood. Liver kinase B1 (LKB1) is a key activator of AMP-activated protein kinase and possibly other signaling pathways that oppose myocardial hypertrophy and failure. We hypothesized that LKB1 is essential to the heart's ability to withstand the metabolic stress of dietary excess.
  
  
  RESULTS
  Mice heterozygous for cardiac LKB1 were fed a control diet or a high-fat, high-sucrose diet for 4 months. On the control diet, cardiac LKB1 hearts had normal structure and function. After 4 months of the high-fat, high-sucrose diet, there was left ventricular hypertrophy and diastolic dysfunction in wild-type mice. In cardiac LKB1 (versus wild-type) mice, high-fat, high-sucrose feeding caused more hypertrophy (619 versus 553 μm(2), P<0.05), the de novo appearance of systolic dysfunction (left ventricular ejection fraction; 41% versus 59%, P<0.01) with left ventricular dilation (3.6 versus 3.2 mm, P<0.05), and more severe diastolic dysfunction with progression to a restrictive filling pattern (E/A ratio; 5.5 versus 1.3, P=0.05). Myocardial dysfunction in hearts of cardiac LKB1 mice fed the high-fat, high-sucrose diet was associated with evidence of increased apoptosis and apoptotic signaling via caspase 3 and p53/PUMA (p53 upregulated modulator of apoptosis) and more severe mitochondrial dysfunction.
  
  
  CONCLUSIONS
  Partial deficiency of cardiac LKB1 promotes the adverse effects of a high-fat, high-sucrose diet on the myocardium, leading to worsening of diastolic function and the de novo appearance of systolic dysfunction. LKB1 plays a key role in protecting the heart from the consequences of metabolic stress.
authors.affiliation: Myocardial Biology Unit, Boston Medical Center and Boston University School of Medicine, Boston, MA (E.J.M., T.C., A.E., A.S., F.Q., I.L., K.W., X.S., A.V., D.C., W.S.C.) Whitaker Cardiovascular Institute, Boston Medical Center and Boston University School of Medicine, Boston, MA (E.J.M., F.Q., M.B., R.A.C., K.W., W.S.C.).
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Miller
authors.affiliation: Myocardial Biology Unit, Boston Medical Center and Boston University School of Medicine, Boston, MA (E.J.M., T.C., A.E., A.S., F.Q., I.L., K.W., X.S., A.V., D.C., W.S.C.).
authors.forename: Timothy
authors.initials: T
authors.lastname: Calamaras
authors.affiliation: Myocardial Biology Unit, Boston Medical Center and Boston University School of Medicine, Boston, MA (E.J.M., T.C., A.E., A.S., F.Q., I.L., K.W., X.S., A.V., D.C., W.S.C.).
authors.forename: Aly
authors.initials: A
authors.lastname: Elezaby
authors.affiliation: Myocardial Biology Unit, Boston Medical Center and Boston University School of Medicine, Boston, MA (E.J.M., T.C., A.E., A.S., F.Q., I.L., K.W., X.S., A.V., D.C., W.S.C.).
authors.forename: Aaron
authors.initials: A
authors.lastname: Sverdlov
authors.affiliation: Myocardial Biology Unit, Boston Medical Center and Boston University School of Medicine, Boston, MA (E.J.M., T.C., A.E., A.S., F.Q., I.L., K.W., X.S., A.V., D.C., W.S.C.) Whitaker Cardiovascular Institute, Boston Medical Center and Boston University School of Medicine, Boston, MA (E.J.M., F.Q., M.B., R.A.C., K.W., W.S.C.).
authors.forename: Fuzhong
authors.initials: F
authors.lastname: Qin
authors.affiliation: Myocardial Biology Unit, Boston Medical Center and Boston University School of Medicine, Boston, MA (E.J.M., T.C., A.E., A.S., F.Q., I.L., K.W., X.S., A.V., D.C., W.S.C.).
authors.forename: Ivan
authors.initials: I
authors.lastname: Luptak
authors.affiliation: Myocardial Biology Unit, Boston Medical Center and Boston University School of Medicine, Boston, MA (E.J.M., T.C., A.E., A.S., F.Q., I.L., K.W., X.S., A.V., D.C., W.S.C.).
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: Myocardial Biology Unit, Boston Medical Center and Boston University School of Medicine, Boston, MA (E.J.M., T.C., A.E., A.S., F.Q., I.L., K.W., X.S., A.V., D.C., W.S.C.).
authors.forename: Xinxin
authors.initials: X
authors.lastname: Sun
authors.affiliation: Myocardial Biology Unit, Boston Medical Center and Boston University School of Medicine, Boston, MA (E.J.M., T.C., A.E., A.S., F.Q., I.L., K.W., X.S., A.V., D.C., W.S.C.).
authors.forename: Andrea
authors.initials: A
authors.lastname: Vijay
authors.affiliation: Myocardial Biology Unit, Boston Medical Center and Boston University School of Medicine, Boston, MA (E.J.M., T.C., A.E., A.S., F.Q., I.L., K.W., X.S., A.V., D.C., W.S.C.).
authors.forename: Dominique
authors.initials: D
authors.lastname: Croteau
authors.affiliation: Vascular Biology Unit, Boston Medical Center and Boston University School of Medicine, Boston, MA (M.B., R.A.C.) Whitaker Cardiovascular Institute, Boston Medical Center and Boston University School of Medicine, Boston, MA (E.J.M., F.Q., M.B., R.A.C., K.W., W.S.C.).
authors.forename: Markus
authors.initials: M
authors.lastname: Bachschmid
authors.affiliation: Vascular Biology Unit, Boston Medical Center and Boston University School of Medicine, Boston, MA (M.B., R.A.C.) Whitaker Cardiovascular Institute, Boston Medical Center and Boston University School of Medicine, Boston, MA (E.J.M., F.Q., M.B., R.A.C., K.W., W.S.C.).
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cohen
authors.affiliation: Whitaker Cardiovascular Institute, Boston Medical Center and Boston University School of Medicine, Boston, MA (E.J.M., F.Q., M.B., R.A.C., K.W., W.S.C.).
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.affiliation: Myocardial Biology Unit, Boston Medical Center and Boston University School of Medicine, Boston, MA (E.J.M., T.C., A.E., A.S., F.Q., I.L., K.W., X.S., A.V., D.C., W.S.C.) Whitaker Cardiovascular Institute, Boston Medical Center and Boston University School of Medicine, Boston, MA (E.J.M., F.Q., M.B., R.A.C., K.W., W.S.C.).
authors.forename: Wilson S
authors.initials: WS
authors.lastname: Colucci
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D003971:Diastole; D059305:Diet, High-Fat; D019422:Dietary Sucrose; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000201:enzymology* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D013599:Systole; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D051017:Apoptosis Regulatory Proteins; D019422:Dietary Sucrose; C488588:PUMA protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: diabetes mellitus; heart failure; metabolism; obesity