Search

Exercise training has been reported to exert beneficial effects on cardiac function and to reduce morbidity and mortality of chronic heart failure (HF). Augmented sympathetic nervous system (SNS) activity, leading to elevated circulating catecholamine (CA) levels, is a hallmark of chronic HF that significantly aggravates this disease. Exercise training has been shown to also reduce SNS overactivity in HF, but the underlying molecular mechanism(s) remain unidentified. We recently reported that adrenal G protein-coupled receptor kinase-2 (GRK2), an enzyme that regulates the sympathoinhibitory α2-adrenoceptors (α2-ARs) present in the CA-producing adrenal medulla, is upregulated in HF, contributing to the chronically elevated CA levels and SNS activity of the disease. In the present study, we tested whether exercise training can affect the adrenal GRK2-α2-AR-CA production system in the context of HF. For this purpose, a 10-wk-long exercise training regimen of adult male Sprague-Dawley rats starting at 4 wk postmyocardial infarction (post-MI) was employed, and examination at the end of this treatment period revealed significant amelioration of β-AR-stimulated contractility in response to exercise training, accompanied by cardiac GRK2 reduction and restoration of circulating plasma CA levels. Importantly, adrenal GRK2 expression (72 ± 5% reduction vs. post-MI untrained) and α2-AR number were also restored after exercise training in post-MI animals. These results suggest that exercise training restores the adrenal GRK2-α2-AR-CA production axis, and this might be part of the mechanism whereby this therapeutic modality normalizes sympathetic overdrive and impedes worsening of the failing heart.

β-2 adrenergic receptor (β-2AR) plays a pivotal role in endothelial cell proliferation and promotes angiogenesis in response to hindlimb ischemia. Desensitization/uncoupling of cardiac β-2AR represents a well established phenomenon in heart failure (HF). In this study we aimed to investigate the role of β-2AR in the impairment of angiogenic processes occurring in the failing myocardium. To this purpose, we explored the angiogenic effects of β-2AR in a rat model of post-myocardial infarction (MI) HF. Cardiac adenoviral-mediated β-2AR overexpres-sion has been obtained via direct intramyocardial injection (4 x 10 11 PFU) 4 weeks after MI. We also extended our observation to β-2AR knockout (β2KO) mice developing HF after large anterior MI (infarct size 45 ± 6%). Cardiac β-2AR overexpression in HF rats markedly increased capillary and arteriolar length density, and induced larger left ventricular (LV) hypertrophic responses than that observed in untreated HF animals. Such LV adaptive remodelling was associated to reduced LV diameters and improved cardiac LV fractional shortening (FS) and +dP/dt. At molecular level, cardiac β-2AR gene transfer induced sustained activation of p-Akt and S6 kinase (S6K) phosphorylation and increased p-eNOS and VEGF levels that were instead reduced in untreated HF rats. In β2KO mice, we found a ~25% reduction of cardiac capillary and arteriolar density compared to WT mice. In β2KO mice, MI was associated with a dramatically higher 21-day mortality compared to WT (70% vs 30%, respectively). Survivors β2KO mice showed increased LV end diastolic and systolic diameters, and worse global cardiac contractility compared to controls. Cardiac Akt activation, S6K phosphorylation, p-eNOS, and VEGF-A production were significantly blunted in HF β2KO mice. Conclusions. β-2ARs play an important role in regulating angiogenic responses in post-MI HF hearts. The activation of Akt signal transduction pathway seems to be strongly involved in these mechanisms.

Aims: We investigated whether exercise training could promote angiogenesis and improve blood perfusion and left ventricular (LV) remodelling of the post-myocardial infarction (MI) failing heart. We also explored the contribution of ameliorated beta-adrenergic receptor signalling and function on the overall improvement of cardiac contractility reserve induced by exercise.Methods and results: Adult Wistar male rats were randomly assigned to one of four experimental groups. Sham-operated and post-MI heart failure (HF) rats were housed under sedentary conditions or assigned to 10-weeks of a treadmill exercise protocol. At 4 weeks after MI, sedentary HF rats showed LV eccentric hypertrophy, marked increase of LV diameters associated with severely impaired fractional shortening (14 +/- 5%), increased LV end diastolic pressure (20.9 +/- 2.6 mmHg), and pulmonary congestion. In addition, cardiac contractile responses to adrenergic stimulation were significantly blunted. In trained HF rats, exercise was able to (i) reactivate the cardiac vascular endothelial growth factor pathway with a concurrent enhancement of myocardial angiogenesis, (ii) significantly increase myocardial perfusion and coronary reserve, (iii) reduce cardiac diameters, and (iv) improve LV contractility in response to adrenergic stimulation. This latter finding was also associated with a significant improvement of cardiac beta-adrenergic receptor downregulation and desensitization.Conclusions: Our data indicate that exercise favourably affects angiogenesis and improves LV remodelling and contractility reserve in a rat model of severe chronic HF.

Alterations in signal transduction pathway of G-protein-coupled receptors (GPCRs) have been found in the cerebrocortex and in the peripheral cultured tissues of patients with Alzheimer's disease (AD). The G-protein-coupled receptor kinase-2 (GRK2) plays an important role in regulating the GPCRs signaling: its increased expression is associated with receptor desensitization. The aim of this study was to explore GRK2 levels in peripheral lymphocytes of AD patients and to establish a correlation between lymphocyte protein concentrations and the degree of cognitive impairment. GRK2 mRNA and protein expression were evaluated in the lymphocytes of AD patients with mild or moderate/severe cognitive impairment and in age-matched healthy subjects. Both GRK2 mRNA and protein expression were higher in AD patients lymphocytes compared to controls. Furthermore, lymphocyte GRK2 levels were significantly correlated to the degree of cognitive decline. Our preliminary data suggest that GRK2 is involved in GPCRs coupling dysfunction observed in AD patients. Further studies are needed in order to verify whether the lymphocyte GRK2 might be utilized as a novel biomarker in AD diagnosis and clinical monitoring.

Exercise training and beta-blocker treatment ameliorate age-dependent impairment of beta-adrenergic receptor signaling and enhance cardiac responsiveness to adrenergic stimulation. Am J Physiol Heart Circ Physiol 293: H1596–H1603, 2007. First published June 8, 2007; doi:10.1152/ajpheart.00308.2007.— Cardiac beta-adrenergic receptor (*-AR) signaling and left ventricular (LV) responses to beta-AR stimulation are impaired with aging. It is shown that exercise and beta-AR blockade have a favorable effect on cardiac and vascular *-AR signaling in several cardiovascular diseases. In the present study, we examined the effects of these two different strategies on *-AR dysregulation and LV inotropic reserve in the aging heart. Forty male Wistar-Kyoto aged rats were randomized to sedentary, exercise (12 wk treadmill training), metoprolol (250 mg kg-1 day-1 for 4 wk), and exercise plus metoprolol treatment protocols. Ten male Wistar- Kyoto sedentary young rats were also used as a control group. Old trained, old metoprolol-treated, and old trained plus metoprololtreated rats showed significantly improved LV maximal and minimal first derivative of the pressure rise responses to beta-AR stimulation (isoproterenol) compared with old untrained animals. We found a significant reduction in cardiac sarcolemmal membrane beta-AR density and adenylyl cyclase activity in old untrained animals compared with young controls. Exercise training and metoprolol, alone or combined, restored cardiac beta-AR density and G-protein-dependent adenylyl cyclase activation in old rats. Although cardiac membrane G-proteinreceptor kinase 2 levels were not upregulated in untrained old compared with young control rats, both exercise and metoprolol treatment resulted in a dramatic reduction of G-protein-receptor kinase 2 protein levels, which is a further indication of beta-AR signaling amelioration in the aged heart induced by these treatment modalities. In conclusion, we demonstrate for the first time that exercise and beta-AR blockade can similarly ameliorate beta-AR signaling in the aged heart, leading to improved beta-AR responsiveness and corresponding LV inotropic reserve.