Negative impact of β-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms.
β-Arrestin (βarr)-1 and β-arrestin-2 (βarrs) are universal G-protein-coupled receptor adapter proteins that negatively regulate cardiac β-adrenergic receptor (βAR) function via βAR desensitization and downregulation. In addition, they mediate G-protein-independent βAR signaling, which might be beneficial, for example, antiapoptotic, for the heart. However, the specific role(s) of each βarr isoform in cardiac βAR dysfunction, the molecular hallmark of chronic heart failure (HF), remains unknown. Furthermore, adrenal βarr1 exacerbates HF by chronically enhancing adrenal production and hence circulating levels of aldosterone and catecholamines. Herein, we sought to delineate specific roles of βarr1 in post-myocardial infarction (MI) HF by testing the effects of βarr1 genetic deletion on normal and post-MI cardiac function and morphology. We studied βarr1 knockout (βarr1KO) mice alongside wild-type controls under normal conditions and after surgical MI. Normal (sham-operated) βarr1KO mice display enhanced βAR-dependent contractility and post-MI βarr1KO mice enhanced overall cardiac function (and βAR-dependent contractility) compared with wild type. Post-MI βarr1KO mice also show increased survival and decreased cardiac infarct size, apoptosis, and adverse remodeling, as well as circulating catecholamines and aldosterone, compared with post-MI wild type. The underlying mechanisms, on one hand, improved cardiac βAR signaling and function, as evidenced by increased βAR density and procontractile signaling, via reduced cardiac βAR desensitization because of cardiac βarr1 absence, and, on the other hand, decreased production leading to lower circulating levels of catecholamines and aldosterone because of adrenal βarr1 absence. Thus, βarr1, via both cardiac and adrenal effects, is detrimental for cardiac structure and function and significantly exacerbates post-MI HF.
Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, 3200 S University Dr, HPD Bldg/Room 1338, Fort Lauderdale, FL 33328. al806@nova.edu.
Ashley
A
Bathgate-Siryk
Samalia
S
Dabul
Krunal
K
Pandya
Karlee
K
Walklett
Giuseppe
G
Rengo
Alessandro
A
Cannavo
Claudio
C
De Lucia
Daniela
D
Liccardo
Erhe
E
Gao
Dario
D
Leosco
Walter J
WJ
Koch
Anastasios
A
Lymperopoulos
D000311:Adrenal Glands / Q000502:physiology*; D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology* / Q000401:mortality / Q000503:physiopathology*; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000150:complications* / Q000401:mortality / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology; D013318:Stroke Volume / Q000502:physiology; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D002395:Catecholamines; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000450:Aldosterone
aldosterone; catecholamines; knockout mice; β-arrestin-1