Domain‐Specific Roles for GRK2 in Cardiac Hypertrophy and Heart Failure
Authors: Schumacher Sarah M , Gao Erhe , Chuprun J Kurt , Koch Walter J 
Published: November 2023

Heart failure is a leading cause of death worldwide and a growing burden on public health. Several co‐morbid conditions, including chronic hypertension and myocardial infarction, culminate in heart failure development. While significant advances have been made in stabilizing and relieving patient symptoms, the underlying mechanisms of cardiac remodeling and decompensation remain a focus of research efforts towards therapeutic development. Signaling via G protein‐coupled receptors (GPCRs) is critical for normal heart function and is tightly controlled by GPCR kinases (GRKs) with one in particular, GRK2 (originally known as βARK1), being intimately involved in heart failure progression. In addition to its well‐characterized role in the regulation of GPCRs, ongoing research has demonstrated great diversity in the functional roles of GRK2, including phosphorylation of non‐GPCR substrates and numerous phosphorylation‐independent regulatory binding partners. I have recently investigated GRK2 amino terminal binding interactions through the generation of transgenic (Tg) mice with cardiac‐targeted expression of the amino‐terminal peptide βARKnt (residues 50–145). In a murine model of trans‐aortic constriction (TAC)‐induced pressure overload, echocardiography revealed increased left ventricular posterior wall thickness (1.37 ± 0.01 in NLC and 1.57 ± 0.02 in Tg mice during systole; n = 17, 16 respectively) and left ventricular mass in TgβARKnt compared to non‐transgenic littermate controls (NLC) 4 weeks after TAC or Sham surgery. Interestingly, despite enhanced hypertrophy at baseline and after acute pressure overload, the progression to heart failure was paradoxically inhibited in TgβARKnt mice during chronic pressure overload with preserved cardiac function (% Ejection Fraction 37.3 ± 2.0 in NLC and 57.3 ± 0.7 in Tg mice; n = 11, 10 respectively) and left ventricular wall thickness during systole (1.2 ± 0.02 in NLC and 1.5 ± 0.02 in Tg mice; n = 11, 10 respectively). Further, βARKnt expression limited adverse left ventricular remodeling, with reduced interstitial fibrosis (% area fibrosis 9.2 ± 0.8 in NLC (11 hearts, 191 images) and 4.1 ± 0.4 in Tg mice (9 hearts, 136 images)) and preserved β‐adrenergic receptor density (BMax (fmol/mg) of 38.5 ± 1.5 in NLC and 45.0 ± 4.6 in Tg Sham, 31.1 ± 1.1 in NLC and 35.4 ± 1.7 in Tg TAC mice; n = 7, 8, 11, 12 respectively) 4 weeks after surgery. The effect of cardiac βARKnt expression was not consistent with alterations in GRK2 activity at GPCRs as neither GRK2 peptide inhibition (TgβARKct) nor GRK2 overexpression alter hypertrophy 4 weeks after TAC, and overexpression hastens heart failure development. These data support the idea that the βARKnt peptide embodies a distinct functional interaction and that βARKnt‐mediated regulation of β‐adrenergic receptor density may provide a novel means of cardioprotection during pressure‐overload induced heart failure. This research is currently focused on elucidating unique binding partners for the βARKnt peptide, with a focus on modulators of β‐adrenergic receptor density, markers of physiological hypertrophy, and exercise tolerance. Mapping these functional protein‐binding interactions and whether they are altered during disease will expand our understanding of cardiovascular signaling pathways, and as our understanding of the underlying dysfunction of the myocardium increases, so does our ability to target the mechanisms responsible for heart failure progression.

Support or Funding Information

Brody Family Medical Trust Fund Fellowship and K99 HL132882 (SMS); R37 HL061690, P01 HL075443, and P01 HL108806 (WJK).