title: Targeted deletion of PTEN in cardiomyocytes renders cardiac contractile dysfunction through interruption of Pink1-AMPK signaling and autophagy.
abstract: Phosphatase and tensin homolog (PTEN) deleted from chromosome 10 has been implicated in the maintenance of cardiac homeostasis although the underlying mechanism(s) remains elusive. We generated a murine model of cardiomyocyte-specific knockout of PTEN to evaluate cardiac geometry and contractile function, as well as the effect of metformin on PTEN deficiency-induced cardiac anomalies, if any. Cardiac histology, autophagy and related signaling molecules were evaluated. Cardiomyocyte-specific PTEN deletion elicited cardiac hypertrophy and contractile anomalies (echocardiographic and cardiomyocyte contractile dysfunction) associated with compromised intracellular Ca(2+) handling. PTEN deletion-induced cardiac hypertrophy and contractile anomalies were associated with dampened phosphorylation of PTEN-inducible kinase 1 (Pink1) and AMPK. Interestingly, administration of AMPK activator metformin (200mg/kg/d, in drinking H2O for 4weeks) rescued against PTEN deletion-induced geometric and functional defects as well as interrupted autophagy and autophagic flux in the heart. Moreover, metformin administration partially although significantly attenuated PTEN deletion-induced accumulation of superoxide. RNA interference against Pink1 in H9C2 myoblasts overtly increased intracellular ATP levels and suppressed AMPK phosphorylation, confirming the role of AMPK as a downstream target for PTEN-Pink1. Further scrutiny revealed that activation of AMPK and autophagy using metformin and rapamycin, respectively, rescued against PTEN deletion-induced mechanical anomalies with little additive effect. These data demonstrated that cardiomyocyte-specific deletion of PTEN leads to the loss of Pink1-AMPK signaling, development of cardiac hypertrophy and contractile defect. Activation of AMPK rescued against PTEN deletion-induced cardiac anomalies associated with restoration of autophagy and autophagic flux. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Roe
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Xihui
authors.initials: X
authors.lastname: Xu
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Machender R
authors.initials: MR
authors.lastname: Kandadi
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; Department of Emergency, Qilu Hospital of Shandong University, Jinan, Shandong 250012, PR China.
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Pang
authors.affiliation: Department of Medicine, Division of Renal Disease and Hypertension, University of Colorado Denver, Denver, CO 80262, USA.
authors.forename: Mary C M
authors.initials: MC
authors.lastname: Weiser-Evans
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA. Electronic address: jren@uwyo.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D042541:Intracellular Space / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate; D008687:Metformin; D051059:PTEN Phosphohydrolase; D011494:Protein Kinases; D013481:Superoxides; D000099202:PTEN-Induced Putative Kinase; C487757:Pten protein, mouse
keywords: AMPK; Cardiac hypertrophy; Contractile function; PTEN; Pink1