Parallel Changes in Neuronal AT1R and GRK5 Expression Following Exercise Training in Heart Failure

Abstract

Although exercise training (ExT) is an important therapeutic strategy for improving quality of life in patients with chronic heart failure (CHF), the central mechanisms by which ExT is beneficial are not well understood. The angiotensin II type 1 receptor (AT1R) plays a pivotal role in the development of CHF, and is upregulated in a number of tissues due in part to transcription factor nuclear factor kappa B (NF-κB). In addition, AT1R is marked for internalization and recycling via G protein coupled receptor kinase (GRK) phosphorylation. Because previous studies have shown that the beneficial effects of ExT in CHF rely on a reduction in Ang II, we hypothesized ExT would decrease AT1R, GRK5 and NF-κB protein expression in the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) of CHF rats. Following infarction by coronary artery ligation, animals were exercised four weeks post-surgery on a treadmill at a final speed of 25 m/min for 60 minutes, 5 days/week for 6 weeks. Western blot analysis of PVN and RVLM micropunches revealed an upregulation of AT1R, GRK5 and NF-κB in the infarcted group that was reversed by ExT. Furthermore, the relative expression of phosphorylated AT1R and AT1R/GRK5 physical association was increased in the CHF sedentary group, and reversed by ExT. Overexpression of GRK5 in cultured CATH.a neurons blunted angiotensin II-mediated upregulation of AT1R and NF-κB; conversely, silencing of GRK5 exacerbated angiotensin II-mediated AT1R and NF-κB upregulation. Taken together, increased GRK5 may regulate AT1R expression in CHF, and ExT mitigates AT1R and its pathway components.

Neurotransmission to parasympathetic cardiac vagal neurons in the brain stem is altered with left ventricular hypertrophy-induced heart failure

“…The discharge rates of neurons likely involved in sympathetic activity within the dorsolateral periaqueductal gray neurons are augmented in HF compared with control rats (42). Other work has shown changes in sympathetic neurons in the rostral ventrolateral medulla with upregulation of ANG II type 1 receptors, G protein-coupled receptor kinase 5, and NF-B expression (18) as well as increased firing activity of PVN neurons that were antidromically activated from the sympathetic target in the rostral ventrolateral medulla (43). The increased activity of PVN presympathetic neurons with HF may be due to many causes, including diminished endothelial nitric oxide synthase expression and nitric oxide synthase-derived nitric oxide availability in the PVN (3), enhanced expression of chemokines (such as chemokine stromal cell-derived factor 1) (40), and proinflammatory cytokines and ANG II type 1 receptors in the PVN in HF animals (46) as well as a reduction in the frequency of spontaneous IPSCs in rostral ventrolateral medulla-projecting PVN neurons (19).…”

Carotid Chemoreceptor Ablation Improves Survival in Heart Failure

“…Cardiac function was determined by echocardiography (Vevo 770; Visualsonics, Inc.) as previously described (13,17). M-mode tracings were recorded through the anterior and posterior LV walls, and anterior and posterior wall thicknesses (end-diastolic and end-systolic) and LV internal dimensions were measured.…”

“…M-mode tracings were recorded through the anterior and posterior LV walls, and anterior and posterior wall thicknesses (end-diastolic and end-systolic) and LV internal dimensions were measured. Rats with ejection fraction of less than 45% were considered to be in CHF (13,17). …”

Central mechanisms for exercise training-induced reduction in sympatho-excitation in chronic heart failure

“…NFkB is a protein dimer that is a transcription factor for a number of other pro-inflammatory cytokines and stress response genes (Kumar et al, J Mol Med (2004) 82:434–448). It is not clear if exercise training alters this pathway but data from our laboratory indicates that NFkB is reduced following exercise training in animals with CHF (figure 2)(Haack et al, 2012). In addition, the regulation of AT1R turnover may be affected by changes in the G-protein coupled receptor, GRK5 (Haack et al, 2012).…”

“…It is not clear if exercise training alters this pathway but data from our laboratory indicates that NFkB is reduced following exercise training in animals with CHF (figure 2)(Haack et al, 2012). In addition, the regulation of AT1R turnover may be affected by changes in the G-protein coupled receptor, GRK5 (Haack et al, 2012). Importantly, exercise training in heart failure also reduces cytokine levels, a major source of NFkB activation (Conraads et al, 2002; Gielen et al, 2003; LeMaitre et al, 2004).…”