Downregulation of G protein-coupled receptor kinase 2 levels enhances cardiac insulin sensitivity and switches on cardioprotective gene expression patterns

• Published in: Biochimica et biophysica acta Vol. 1842; no. 12; pp. 2448 - 2456
• Main Authors: Lucas, Elisa, Jurado-Pueyo, María, Fortuño, María A., Fernández-Veledo, Sonia, Vila-Bedmar, Rocío, Jiménez-Borreguero, Luis J., Lazcano, Juan J., Gao, Ehre, Gómez-Ambrosi, Javier, Frühbeck, Gema, Koch, Walter J., Díez, Javier, Mayor, Federico, Murga, Cristina
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2014
• Subjects: Animals; Blotting, Western; Cardiac hypertrophy; Cardiomegaly - genetics; Cardiomegaly - metabolism; Cell Membrane - drug effects; Cell Membrane - metabolism; Diet, High-Fat - adverse effects; Down-Regulation; G protein-coupled receptors; G-Protein-Coupled Receptor Kinase 2 - genetics; G-Protein-Coupled Receptor Kinase 2 - metabolism; Gene Expression Profiling - methods; Glucose Transporter Type 4 - metabolism; GRK2; Heart failure; High fat diet; Hypoglycemic Agents - pharmacology; Insulin - pharmacology; Insulin resistance; Insulin Resistance - genetics; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Myocardium - metabolism; Obesity - etiology; Obesity - genetics; Obesity - metabolism; Oligonucleotide Array Sequence Analysis; Phosphorylation - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Heart failure; GRK2; G protein-coupled receptors; HFD; Cardiac hypertrophy; GPCR; IR; Insulin resistance; WT; HF; High fat diet
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2014.09.004

G protein-coupled receptor kinase 2 (GRK2) has recently emerged as a negative modulator of insulin signaling. GRK2 downregulation improves insulin sensitivity and prevents systemic insulin resistance. Cardiac GRK2 levels are increased in human heart failure, while genetically inhibiting GRK2 leads to cardioprotection in mice. However, the molecular basis underlying the deleterious effects of GRK2 up-regulation and the beneficial effects of its inhibition in the heart are not fully understood. Therefore, we have explored the interconnections among a systemic insulin resistant status, GRK2 dosage and cardiac insulin sensitivity in adult (9month-old) animals. GRK2+/− mice display enhanced cardiac insulin sensitivity and mild heart hypertrophy with preserved systolic function. Cardiac gene expression is reprogrammed in these animals, with increased expression of genes related to physiological hypertrophy, while the expression of genes related to pathological hypertrophy or to diabetes/obesity co-morbidities is repressed. Notably, we find that cardiac GRK2 levels increase in situations where insulin resistance develops, such as in ob/ob mice or after high fat diet feeding. Our data suggest that GRK2 downregulation/inhibition can help maintain cardiac function in the face of co-morbidities such as insulin resistance, diabetes or obesity by sustaining insulin sensitivity and promoting a gene expression reprogramming that confers cardioprotection. •GRK2 downregulation enhances insulin signaling in adult mouse hearts.•GRK2+/− adult mice show mild heart hypertrophy with preserved systolic function.•In GRK2+/− hearts, genes related to pathologies or obesity/diabetes are repressed.•GRK2 expression is increased in obese and in high fat diet-fed murine hearts.•Insulin sensitivity is strongly preserved in GRK2+/− hearts after a high-fat diet.