A peptide of the amino-terminus of GRK2 induces hypertrophy and yet elicits cardioprotection after pressure overload

被引:11
作者
Bledzka, Kamila M. [3 ]
Manaserh, Iyad H. [3 ]
Grondolsky, Jessica [3 ]
Pfleger, Jessica [1 ]
Roy, Rajika [1 ]
Gao, Erhe [1 ]
Chuprun, J. Kurt [1 ]
Koch, Walter J. [1 ,2 ]
Schumacher, Sarah M. [3 ]
机构
[1] Temple Univ, Ctr Translat Med, Philadelphia, PA 19122 USA
[2] Temple Univ, Lewis Katz Sch Med, Dept Pharmacol, Philadelphia, PA 19140 USA
[3] Cleveland Clin, Lerner Res Inst, Dept Cardiovasc & Metab Sci, Cleveland, OH 44195 USA
基金
美国国家卫生研究院;
关键词
GRK2; Hypertrophy; Heart failure; Physiological; Proteomics; PHOSPHOTYROSINE-BINDING DOMAIN; ADRENERGIC-RECEPTOR KINASE; RAB-GAP AS160; HEART-FAILURE; CARDIAC-HYPERTROPHY; INSULIN-RESISTANCE; OXIDATIVE STRESS; SKELETAL-MUSCLE; GLUT4; MICE;
D O I
10.1016/j.yjmcc.2021.01.004
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
G protein-coupled receptor (GPCR) kinase 2 (GRK2) expression and activity are elevated early on in response to several forms of cardiovascular stress and are a hallmark of heart failure. Interestingly, though, in addition to its well-characterized role in regulating GPCRs, mounting evidence suggests a GRK2 "interactome" that underlies a great diversity in its functional roles. Several such GRK2 interacting partners are important for adaptive and maladaptive myocyte growth; therefore, an understanding of domain-specific interactions with signaling and regulatory molecules could lead to novel targets for heart failure therapy. Herein, we subjected transgenic mice with cardiac restricted expression of a short, amino terminal fragment of GRK2 (llARKnt) to pressure overload and found that unlike their littermate controls or previous GRK2 fragments, they exhibited an increased left ventricular wall thickness and mass prior to cardiac stress that underwent proportional hypertrophic growth to controls after acute pressure overload. Importantly, despite this enlarged heart, llARKnt mice did not undergo the expected transition to heart failure observed in controls. Further, llARKnt expression limited adverse left ventricular remodeling and increased cell survival signaling. Proteomic analysis to identify llARKnt binding partners that may underlie the improved cardiovascular phenotype uncovered a selective functional interaction of both endogenous GRK2 and llARKnt with AKT substrate of 160 kDa (AS160). AS160 has emerged as a key downstream regulator of insulin signaling, integrating physiological and metabolic cues to couple energy demand to membrane recruitment of Glut4. Our preliminary data indicate that in llARKnt mice, cardiomyocyte insulin signaling is improved during stress, with a coordinate increase in spare respiratory activity and ATP production without metabolite switching. Surprisingly, these studies also revealed a significant decrease in gonadal fat weight, equivalent to human abdominal fat, in male llARKnt mice at baseline and following cardiac stress. These data suggest that the enhanced AS160-mediated signaling in the llARKnt mice may ameliorate pathological cardiac remodeling through direct modulation of insulin signaling within cardiomyocytes, and translate these to beneficial effects on systemic metabolism.
引用
收藏
页码:137 / 153
页数:17
相关论文
共 71 条
[1]   Rab GEFs and GAPs [J].
Barr, Francis ;
Lambright, David G. .
CURRENT OPINION IN CELL BIOLOGY, 2010, 22 (04) :461-470
[2]   Molecular distinction between physiological and pathological cardiac hypertrophy: Experimental findings and therapeutic strategies [J].
Bernardo, Bianca C. ;
Weeks, Kate L. ;
Pretorius, Lynette ;
McMullen, Julie R. .
PHARMACOLOGY & THERAPEUTICS, 2010, 128 (01) :191-227
[3]   Contribution of Impaired Myocardial Insulin Signaling to Mitochondrial Dysfunction and Oxidative Stress in the Heart [J].
Boudina, Sihem ;
Bugger, Heiko ;
Sena, Sandra ;
O'Neill, Brian T. ;
Zaha, Vlad G. ;
Ilkun, Olesya ;
Wright, Jordan J. ;
Mazumder, Pradip K. ;
Palfreyman, Eric ;
Tidwell, Timothy J. ;
Theobald, Heather ;
Khalimonchuk, Oleh ;
Wayment, Benjamin ;
Sheng, Xiaoming ;
Rodnick, Kenneth J. ;
Centini, Ryan ;
Chen, Dong ;
Litwin, Sheldon E. ;
Weimer, Bart E. ;
Abel, E. Dale .
CIRCULATION, 2009, 119 (09) :1272-U111
[4]   Level of G protein-Coupled Receptor Kinase-2 Determines Myocardial Ischemia/Reperfusion Injury via Pro- and Anti-Apoptotic Mechanisms [J].
Brinks, Henriette ;
Boucher, Matthieu ;
Gao, Erhe ;
Chuprun, J. Kurt ;
Pesant, Stephanie ;
Raake, Philip W. ;
Huang, Z. Maggie ;
Wang, Xiaoliang ;
Qiu, Gang ;
Gumpert, Anna ;
Harris, David M. ;
Eckhart, Andrea D. ;
Most, Patrick ;
Koch, Walter J. .
CIRCULATION RESEARCH, 2010, 107 (09) :1140-U197
[5]   Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity [J].
Chadt, Alexandra ;
Leicht, Katja ;
Deshmukh, Atul ;
Jiang, Lake Q. ;
Scherneck, Stephan ;
Bernhardt, Ulrike ;
Dreja, Tanja ;
Vogel, Heike ;
Schmolz, Katja ;
Kluge, Reinhart ;
Zierath, Juleen R. ;
Hultschig, Claus ;
Hoeben, Rob C. ;
Schuermann, Annette ;
Joost, Hans-Georg ;
Al-Hasani, Hadi .
NATURE GENETICS, 2008, 40 (11) :1354-1359
[6]   Deletion of Both Rab-GTPase-Activating Proteins TBC14KO and TBC1D4 in Mice Eliminates Insulin- and AICAR-Stimulated Glucose Transport [J].
Chadt, Alexandra ;
Immisch, Anja ;
de Wendt, Christian ;
Springer, Christian ;
Zhou, Zhou ;
Stermann, Torben ;
Holman, Geoffrey D. ;
Loffing-Cueni, Dominique ;
Loffing, Johannes ;
Joost, Hans-Georg ;
Al-Hasani, Hadi .
DIABETES, 2015, 64 (03) :746-759
[7]   Prodeath Signaling of G Protein-Coupled Receptor Kinase 2 in Cardiac Myocytes After Ischemic Stress Occurs Via Extracellular Signal-Regulated Kinase-Dependent Heat Shock Protein 90-Mediated Mitochondrial Targeting [J].
Chen, Mai ;
Sato, Priscila Y. ;
Chuprun, J. Kurt ;
Peroutka, Raymond J. ;
Otis, Nicholas J. ;
Ibetti, Jessica ;
Pan, Shi ;
Sheu, Shey-Shing ;
Gao, Erhe ;
Koch, Walter J. .
CIRCULATION RESEARCH, 2013, 112 (08) :1121-+
[8]   Mice with AS160/TBC1D4-Thr649Ala Knockin Mutation Are Glucose Intolerant with Reduced Insulin Sensitivity and Altered GLUT4 Trafficking [J].
Chen, Shuai ;
Wasserman, David H. ;
MacKintosh, Carol ;
Sakamoto, Kei .
CELL METABOLISM, 2011, 13 (01) :68-79
[9]   Enhanced contractility and decreased β-adrenergic receptor kinase-1 in mice lacking endogenous norepinephrine and epinephrine [J].
Cho, MC ;
Rao, M ;
Koch, WJ ;
Thomas, SA ;
Palmiter, RD ;
Rockman, HA .
CIRCULATION, 1999, 99 (20) :2702-2707
[10]   A truncation mutation in TBC1D4 in a family with acanthosis nigricans and postprandial hyperinsulinemia [J].
Dash, Satya ;
Sano, Hiroyuki ;
Rochford, Justin J. ;
Semple, Robert K. ;
Yeo, Giles ;
Hyden, Caroline S. S. ;
Soos, Maria A. ;
Clark, James ;
Rodin, Andrew ;
Langenberg, Claudia ;
Druet, Celine ;
Fawcett, Katherine A. ;
Tung, Y. C. Loraine ;
Wareham, Nicolas J. ;
Barroso, Ines ;
Lienhard, Gustav E. ;
O'Rahilly, Stephen ;
Savage, David B. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (23) :9350-9355