β2- and β1-Adrenoceptor Expression Exhibits a Common Regulatory Pattern With GRK2 and GRK5 in Human and Animal Models of Cardiovascular Diseases

Abstract

To explore if genic expression of β(1)- or β(2)-adrenoceptors (ARs) exhibits a common regulatory pattern with G protein-coupled receptor kinase (GRK) 2, GRK3, or GRK5 expression, we determined messenger RNA levels for these genes in different tissues from human and animal models of cardiovascular disease. We measured genic expression by qRT polymerase chain reaction in the left and right ventricles or peripheral blood mononuclear cells from healthy (n = 21), hypertensive (n = 20), heart failure (n = 24), and heart transplanted patients (n = 17) or in left ventricle, peripheral blood mononuclear cells, and kidney from spontaneously hypertensive rats or L-N-methyl-arginine-induced hypertensive rats and their respective controls (n = 4-5). In diseased versus healthy subjects and rats, parallel changes in messenger RNA levels of GRK2 and β(2)-AR or GRK5 and β(1)-AR were observed in each territory. Therefore, without excluding other regulatory mechanisms, the parallelism observed suggests a common regulatory pattern for the β(1)-AR/GRK5 and β(2)-AR/GRK2 genes, which is independent of cellular type or pathology. This highlights the need to focus not only on GRKs but also on β(1)- or β(2)-AR changes to completely understand the involvement of β-AR/GRK pathways in cardiovascular diseases.

RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism

“…A decreased β-AR function has been reported in heart failure, which may also be associated with SAN dysfunction (28). In this case, SAN failure occurs via a decreased β-AR expression, together with an increase in GRK activity in the heart and mirrored in some cases, in peripheral blood mononuclear cells (28)(29)(30)(31), both in humans (28,29,(32)(33)(34)(35) and in experimental models (34)(35)(36)(37)(38). A decreased expression and an increased desensitization of β-AR directly led to a loss of β-adrenergic function in the failing heart (28).…”

G Protein–Coupled Receptor Kinases: Crucial Regulators of Blood Pressure

“…Grk5 knockout mice have impaired glucose tolerance and insulin sensitivity, indicating that GRK5 is a positive regulator of insulin sensitivity . Increased expression of GRK5 is associated with different animal models of hypertension, including Ang II‐, norepinephrine‐, and L‐NAME–induced hypertension . There is a nuclear redistribution of GRK5 in hypertensive heart‐failure‐prone rats .…”

“…92 Increased expression of GRK5 is associated with different animal models of hypertension, including Ang II-, norepinephrine-, and L-NAME-induced hypertension. 93,94 There is a nuclear redistribution of GRK5 in hypertensive heart-failure-prone rats. 95 The physical association of AT 1 R and GRK5 is increased in the heart in congestive heart failure but is reversed by exercise training.…”

β2-Adrenoceptors and GRK2 as Potential Biomarkers in Patients With Chronic Pulmonary Regurgitation

“…Three different GRK isoforms (GRK2, GRK5 and, in a minor proportion, GRK3) are present in the heart and also in peripheral blood mononuclear cells (PBMC) (Vinge et al, 2007; Grisanti et al, 2018) and their expression (especially GRK2) changes as a consequence of the hemodynamic alterations that occur in HF or hypertension (Iaccarino et al, 2005; Penela et al, 2006; Vinge et al, 2007; Izzo et al, 2008; Cohn et al, 2009; Santulli et al, 2011, 2013; Piao et al, 2012; Grisanti et al, 2018). Moreover, it is remarkable that expression of β2-ARs and GRK2 follow a similar pattern of changes in different tissues and pathologies (Montó et al, 2015). Initially, changes in the expression of GRKs and β-ARs were determined in myocytes (endomyocardial biopsies, cardiac explant), but it is also possible to study these changes in PBMC (Iaccarino et al, 2005; Agüero et al, 2008; Oliver et al, 2010).…”