Abstract 1303: GRK2ct Expression in Vascular Smooth Muscle (VSM) Potentates β-Adrenergic Receptor (AR) Mediated Relaxation
Introduction: Elevated levels of G protein-coupled receptor kinase 2 (GRK2) are associated with human hypertension and animal models of the disease. GRK2 is also increased in heart failure (HF). GRK2ct, a peptide inhibitor of GRK2 (last 194 amino acids of GRK2) is effective at rescuing models of HF through its restoration of cardiac βAR signaling.
Hypothesis: Our interest is in investigating the role of VSM GRK2ct to determine if it is an effective antihypertensive strategy.
Methods: We created transgenic mice that express the GRK2ct peptide in VSM using a portion of the SM22 promoter (VSM-GRK2ct). Conscious BP was derived using a fluid-filled indwelling left common carotid artery catheter. In vivo BP response to acute agonist infusion administered via the jugular vein was recorded in anesthetized mice. Vascular reactivity was determined by force displacement in aortic rings after mechanical endothelial cell denudation.
Results: RNA and protein levels verified VSM-specific expression in 2 independent founder lines. Resting conscious BP was unchanged in GRK2ct mice (111±3 mmHg, n=4) compared with non-transgenetic littermate controls (NLCs) (111±4 mmHg, n=6). No change in VSM carotid thickness was observed (NLC: 26±2, n=8 vs VSM-GRK2ct: 33±3, n=4). Heart-to-body weight ratio also remained unaffected (NLC:4.9±0.07mg/g, n=6 vs VSM-GRK2ct: 4.8±0.16mg/g, n=7). In vivo, VSM-GRK2ct mice had a significantly greater reduction in BP with increasing doses of the βAR agonist, isoproterenol (ISO). Relaxation was significantly increased to ISO in isolated thoracic aorta from GRK2ct vs NLC mice. Interestingly, isolated aorta from VSM-GRK2ct mice also had a significantly greater increase in tension in response to the catecholamine norepinephrine.
Conclusions: βAR signaling is compromised in hypertension, likely due in part to elevated GRK2 expression, and our data suggest restoration of VSM βAR signaling by GRK2ct might be a beneficial therapeutic strategy in hypertension.