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GRK5 overexpression in the RVLM of CHF rats improves autonomic imbalance and restores AT1R and Kv4.3 expressions (686.33)
Author(s) -
Haack Karla,
Becker Bryan,
Zucker Irving
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.686.33
Subject(s) - rostral ventrolateral medulla , medicine , endocrinology , heart failure , angiotensin ii , cardiology , receptor , blood pressure , heart rate
Chronic heart failure (CHF) is characterized by an overactive Angiotensin II type 1 receptor (AT1R) signaling axis and autonomic imbalance. AT1R is regulated by its phosphorylation by G protein coupled receptor kinase 5 (GRK5). We have shown previously that AT1R and GRK5 are paradoxically increased and that Kv4.3, a potassium channel involved in neuronal excitability, is decreased in the rostral ventrolateral medulla (RVLM) of rats with CHF. We tested the hypothesis is that GRK5 overexpression in the RVLM improves autonomic imbalance and normalizes AT1R and Kv4.3 expression in CHF. CHF was induced by coronary artery ligation and confirmed by echocardiography. Following implantation of radiotelemetry transducers, two weeks of heart rate (HR), mean arterial pressure (MAP) and metabolic cage data were collected before and after either vehicle (Veh) or lentiviral GRK5 (GRK5) injection into the RVLM. HR was decreased in GRK5 rats compared to Veh (293±6 vs 316±2 bpm) while MAP was unchanged. Urine norepinephrine was decreased in GRK5 vs Veh (113±51 vs 252±89 ng/24hrs). Western blot analyses of RVLM micropunches indicated that GRK5 decreased AT1R expression vs Veh (1.2±0.1 vs 1.8±0.4 a.u.) and increased Kv4.3 expression by almost 50% compared to Veh. Taken together, these data suggest that GRK5 overxpression in the RVLM may be protective in CHF by decreasing sympathetic tone and normalizing AT1R and Kv4.3 imbalance. Grant Funding Source : Supported by NHLBI F32HL116172‐01