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

Abstract

G protein-coupled receptor kinase 2 (GRK2) has arisen as a signaling hub with critical regulatory roles in cardiac function and dysfunction. Cardiac GRK2 levels are elevated during hypertension, cardiac ischemia and heart failure both in humans and in experimental models, while genetic inhibition of GRK2 results cardioprotective in different animal models of these conditions. However, the mechanistic grounds underlying these effects are not completely understood. Recent research has indicated that GRK2 not only phosphorylates and desensitizes G protein-coupled receptors (GPCR) that are important for heart function such as β-adrenergic or angiotensin type 1, but also modulates other pathways relevant for cardiac physiology such as the insulin signaling cascade. Using GRK2 hemizygous (GRK2+/-) mice, we have unveiled that a lower GRK2 dosage promotes enhanced insulin sensitivity in adult murine hearts what correlates with a cardioprotective gene expression profile. Also, GRK2 levels increase in cardiac tissue in well-established experimental models of systemic insulin resistance, such as high fat diet (HFD) feeding or ob/ob mice what parallels the impaired cardiac insulin sensitivity observed in these conditions. Our findings suggest that pathological inputs of different etiology such as increased catecholamine levels or high dietary fat converge in common important nodes key to the progress of the pathology. One such key connecting hub is GRK2, whose enhanced cardiac expression could promote progression towards maladaptive myocardial remodeling and heart failure.To cite this article: Elisa Lucas, et al. Linking cardiac insulin resistance and heart failure: GRK2 as an integrative node.

G Protein-Coupled Receptor Kinase 2 (GRK2) as a Potential Therapeutic Target in Cardiovascular and Metabolic Diseases

“…In addition, GRK2 has emerged as an important modulator of cardiac insulin signaling, which is key for a balanced glucose and fatty acid metabolism in the heart and has cardioprotective features (Lucas et al., 2015; Hullmann et al., 2016; Riehle and Abel, 2016). Increased GRK2 levels worsen glucose uptake after ischemic injury via IRS1 phosphorylation, whereas cardiac-specific GRK2 knockout mice show enhanced heart glucose metabolism (Ciccarelli et al., 2011).…”

“…Increased GRK2 levels worsen glucose uptake after ischemic injury via IRS1 phosphorylation, whereas cardiac-specific GRK2 knockout mice show enhanced heart glucose metabolism (Ciccarelli et al., 2011). Notably, a high fat diet (HFD) promotes cardiac GRK2 accumulation leading to impaired cardiac insulin sensitivity and reduced stimulation of the cardioprotective PI3K/Akt pathway, whereas this effect was prevented in 9-month-old hemizygous GRK2+/− mice, which showed a preserved insulin-dependent downstream signaling and an overall cardioprotective gene expression reprogramming (Lucas et al., 2014, 2015). Therefore, situations of neurohumoral activation and of obesity/insulin-resistance converge in promoting cardiac GRK2 upregulation, which emerges as a potential factor linking insulin-resistant pathological conditions and heart failure.…”

“…In this line, studies in sinusoidal endothelial cells from injured livers demonstrated that Akt physically interacts with GRK2, which inhibits Akt activation and NO production (Liu et al., 2005). Thus, the increased expression of GRK2 observed in vessels from different mouse models of vascular or metabolic diseases (Taguchi et al., 2011a, 2012b) can be an underlying factor that decreases NO bioavailability and contributes to endothelial dysfunction (Lucas et al., 2015). For instance, chronic AngII treatment of C57Bl6 mice upregulates GRK2 in vessels, leads to inhibition of the Akt/eNOS pathway, and thus reduces NO production both basally and after AngII-infusion that finally results in endothelial dysfunction (Avendano et al., 2014).…”