Ping P, Anzai T, Gao M, Hammond H K
Department of Medicine, Veterans Affairs Medical Center-San Diego, California, USA.
Am J Physiol. 1997 Aug;273(2 Pt 2):H707-17. doi: 10.1152/ajpheart.1997.273.2.H707.
We examined alterations in left ventricular (LV) G protein receptor kinase (GRK) and adenylyl cyclase (AC) isoform expression during the development of pacing-induced congestive heart failure (CHF). AC isoform and GRK expression were assessed 4 (mild CHF) and 28 (severe CHF) days after initiation of pacing. LV beta-adrenergic receptor (beta-AR) number and G protein content were unchanged by mild CHF. LV AC isoform mRNA content was unaltered by mild CHF, but there were increases in total GRK activity (P < 0.01), total GRK5 protein content (P < 0.04), and GRK5 mRNA (P = 0.003); total GRK2 protein content and GRK2 mRNA were unchanged. Mild CHF was associated with decreased beta-AR coupling (P < 0.01) and reduced beta-AR stimulation of AC (P < 0.05). Severe CHF was associated with LV beta-AR downregulation (P = 0.0001) and uncoupling (P < 0.001) and marked generalized reduction of AC activity (mean P = 0.01). LV ACVI isoform mRNA content was reduced (P = 0.002), but ACII and ACV isoform mRNA contents were unaffected. Persistent elevations in LV total GRK activity (P < 0.01), total GRK5 protein content (P < 0.001), and GRK5 mRNA (P = 0.01) were found; in contrast, total GRK2 protein content was unchanged and GRK2 mRNA was reduced (P = 0.02). These studies indicate that increased GRK activity is an early charge in heart failure that predates alterations in AC isoform expression. Impaired hormonal stimulation of AC, associated with beta-AR uncoupling, may result from increased GRK5 expression. AC downregulation is isoform specific and accompanies severe but not mild CHF.
我们研究了起搏诱导的充血性心力衰竭（CHF）发展过程中左心室（LV）G蛋白偶联受体激酶（GRK）和腺苷酸环化酶（AC）亚型表达的变化。在起搏开始后的4天（轻度CHF）和28天（重度CHF）评估AC亚型和GRK表达。轻度CHF未改变LVβ-肾上腺素能受体（β-AR）数量和G蛋白含量。轻度CHF未改变LV AC亚型mRNA含量，但总GRK活性增加（P<0.01），总GRK5蛋白含量增加（P<0.04），GRK5 mRNA增加（P = 0.003）；总GRK2蛋白含量和GRK2 mRNA未改变。轻度CHF与β-AR偶联减少（P<0.01）和β-AR对AC的刺激减少（P<0.05）相关。重度CHF与LVβ-AR下调（P = 0.0001）和解偶联（P<0.001）以及AC活性显著普遍降低（平均P = 0.01）相关。LV ACVI亚型mRNA含量降低（P = 0.002），但ACII和ACV亚型mRNA含量未受影响。发现LV总GRK活性持续升高（P<0.01），总GRK5蛋白含量持续升高（P<0.001），GRK5 mRNA持续升高（P = 0.01）；相反，总GRK2蛋白含量未改变，GRK2 mRNA降低（P = 0.02）。这些研究表明，GRK活性增加是心力衰竭的早期变化，早于AC亚型表达的改变。与β-AR解偶联相关的AC激素刺激受损可能是由于GRK5表达增加所致。AC下调具有亚型特异性，且伴随重度而非轻度CHF。
