Peripheral g-protein-coupled receptor kinase 2 (GRK2) expression reflects cardiac remodeling, mitochondrial dysfunction, and exercise capacity in heart failure

Abstract Background G-protein coupled receptor kinase 2 (GRK2) is a serine/threonine kinase that regulates various intracellular signaling pathways. It plays a key role in modulating the catecholaminergic response mediated by β-adrenergic receptors, leading to receptor desensitization and downregulation, which are hallmark features of chronic heart failure (HF). A strong positive correlation between GRK2 levels in lymphocytes and cardiac tissue has been previously reported, indicating that peripheral GRK2 levels might reflect myocardial pathology. Purpose We aimed to assess the correlation between GRK2 levels in Peripheral Mononuclear blood cells (PBMC), cardiac structural remodeling, and exercise capacity in patients with HF. Methods We enrolled patients with chronic HF who underwent echocardiography and cardiopulmonary exercise testing (C-PET) to assess left ventricular volume (LVEDVi) and exercise capacity (%VO2max), respectively. GRK2 levels were evaluated in peripheral blood mononuclear cells (PBMCs) by Western Blot (WB) analysis, using blood samples collected before and after C-PET. Western blot quantification of GRK2 was normalized to β-actin as a loading control, and results were reported as fold increase (GRK2-FI) compared to baseline/control values. High-resolution respirometry (substrate–uncoupler–inhibitor titration protocol) was performed on freshly isolated PBMCs to assess mitochondrial function parameters, including basal respiration, LEAK, electron transport system (ETS) capacity. Substrates and inhibitors used included oligomycin, rotenone, and antimycin A to isolate complex-specific fluxes. Associations between GRK2 expression, respirometry indices, LVEDVi, and %VO₂max were then examined. Results A significant negative correlation was observed between %VO₂max and LVEDVi, confirming that patients with more pronounced ventricular dilation exhibited reduced exercise. Peripheral GRK2 levels also negatively correlated with LVEDVi, indicating that GRK2 expression may serve as a marker of cardiac remodeling. Conversely, the relationship between GRK2 and %VO2max is not entirely clear, although they seem to share a common trend. Moreover, patients who failed to show an increase in GRK2 expression following CPET displayed reduced mitochondrial respiratory capacity in PBMCs, which correlated with lower exercise performance (%VO₂max). Conclusions Our findings suggest that GRK2 expression in PBMCs mirrors exercise capacity and myocardial remodeling in patients with HF. Demonstrating a link between PBMC GRK2 expression, mitochondrial respiratory dysfunction, and reduced exercise capacity would support PBMC bioenergetic and signaling markers as a mirror of systemic and myocardial pathophysiology in HF, with potential utility for risk stratification and monitoring of therapeutic interventions.