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

Abstract

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 (9 month-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.

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

“…ERK axis activation could be part of the cardioprotective gene expression program initiated by GRK2 inhibition (12,13,41). Concomitantly, the expression of heart failure-promoting Pparg targets was blunted, and the appearance of the dysfunctional cardiac substrate metabolism was retarded.…”

“…Because GRK2 inhibition also mediated the down-regulation of FASN-dependent cardio-lipotoxicity, patients with high morbidity and multiple risk factors may benefit from GRK2 inhibition. The additional insulin sensitivityenhancing activity of GRK2 inhibition (13,58) may further increase the value of such a strategy.…”

“…By generation of transgenic mice, we found that FASN transgenic mice developed a heart failure-like phenotype with impaired cardiomyocyte substrate use. In search for a treatment approach for the disturbed cardiac substrate metabolism, we focused on the role of GRK2 inhibition because GRK2 inhibition could counteract cardiolipotoxicity by promotion of a cardiomyocyte survival program (12,13) and resensitization of the cardioprotective adiponectin receptor 1 (14 -16). For GRK2 inhibition in vivo, we used GRKInh, a small peptide inhibitor derived from the first intracellular loop of the ␤2-adrenergic receptor (12,17).…”

Linking Cardiac Insulin Resistance and Heart Failure: Grk2 as an Integrative Node

“…Given the important role of this cascade in the heart, and the increased GRK2 cardiac levels detected in pathological conditions, we have studied insulin sensitivity in the cardiac tissue of 9 month-old WT mice compared to their GRK2+/-littermates. We have observed that GLUT4 translocation and glucose uptake as well as insulin-dependent Akt and p70S6K activation were impaired in WT but not in GRK2+/-animals [12] . Interestingly, although GRK2+/-mice displayed a larger cardiac area and cardiomyocyte diameter, they did not exhibit pathological cardiac hypertrophy.…”

Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure

“…Indeed, deletion of half the amount of GRK-2 gene expression systemically in mice protected against high-fat diet (HFD)-induced insulin resistance and obesity (GarciaGuerra et al 2010), as well as enhanced cardiac insulinstimulated Akt phosphorylation and glut-4 membrane translocation and reduced cardiac steatosis and fibrosis (Lucas et al 2014(Lucas et al , 2016. By contrast, overexpression of GRK2 in cardiomyocytes attenuated insulin-induced Akt phosphorylation and glut-4 membrane translocation (Ciccarelli et al 2011).…”