Adrenal GRK2 lowering is an underlying mechanism for the beneficial sympathetic effects of exercise training in heart failure

Abstract

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 alpha(2)-adrenoceptors (alpha(2)-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-alpha(2)-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 beta-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 + or - 5% reduction vs. post-MI untrained) and alpha(2)-AR number were also restored after exercise training in post-MI animals. These results suggest that exercise training restores the adrenal GRK2-alpha(2)-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.

Improvement of vascular insulin sensitivity by downregulation of GRK2 mediates exercise-induced alleviation of hypertension in spontaneously hypertensive rats

“…In the present study, we found that exercise training for 10 wk significantly reduced GRK2 expression and activity in SHRs. This is consistent with the reports that GRK2 was downregulated by physical exercise in the heart and kidney (20,26). Importantly, we implicated a causal role for GRK2 by overexpression and knockdown or inhibition of GRK2 in organ culture of mesenteric arteries.…”

Exercise attenuates inflammation and limits scar thinning after myocardial infarction in mice

“…These observations concur with previous studies investigating the effect of exercise after MI on the hypertrophic response in rodents (13,14,33) and humans (21,32,56). In contrast, Rengo et al (62) documented increased LV hypertrophy after 10-wk endurance training after MI in mice. These diverging observations may be attributed to different training protocols.…”

“…In contrast, Rengo et al (62) made use of a daily treadmill training of defined duration and O 2 consumption, starting much later (4 wk) after MI induction, when the maladaptive remodeling process may already have been established. Some studies in animal models and humans have reported exercise-mediated adverse effects on LV dilatation when started early after a large MI (19,37) and neutral or beneficial effects when initiated late after large MI (41,55,62). However, it has to be taken into consideration that adverse effects of endurance training on LV dimensions were only documented in mice subjected to swimming, which may be a more intense (and potentially harmful) stress compared with voluntary treadmill running (19).…”

Targeting the β-Adrenergic Receptor System Through G-Protein–Coupled Receptor Kinase 2: A New Paradigm for Therapy and Prognostic Evaluation in Heart Failure

“…GRK2 upregulation in chromaffin cells of the adrenal medulla was the primary cause of the lack of ␣ 2 AR-mediated inhibition of catecholamine release; indeed, GRK2 inhibition resulted in the restoration of negative feedback on catecholamine release by ␣ 2 AR activation. The crucial role for GRK2 in catecholamine secretion modulation in the adrenal gland has been further confirmed by other studies, [32][33][34] indicating that the effects of "pathological" hyperactivation of GRK2 in HF lie not only in impaired cardiac function but also in unbalanced systemic homeostasis/organ cross-talk due to excessive desensitization of neurohormonal receptors. 35 …”