The expression of calcium/calmodulin-dependent kinase IV (CaMKIV) was hitherto thought to be confined to the nervous system. However, a recent genome-wide analysis indicated an association between hypertension and a single-nucleotide polymorphism (rs10491334) of the human CaMKIV gene (CaMK4), which suggests a role for this kinase in the regulation of vascular tone

Myocardial GRK2 expression and activity are mirrored by lymphocyte levels of this kinase, and its elevation in HF is associated with the loss of beta-AR responsiveness and appears to increase with disease severity. Therefore, lymphocytes may provide a surrogate for monitoring cardiac GRK2 in human HF.

Our results suggest that GRK2 mediates adrenergic IRES and that inhibition of GRK2 activity leads to increased Ins sensitivity both in cells and in animal model of IRES.

Metabolic stimuli such as insulin and insulin like growth factor cause cellular accumulation of G protein Coupled Receptor Kinase 2 (GRK2), which in turn is able to induce insulin resistance. Here we show that in fibroblasts, GRK2 is able to increase ATP cellular content by enhancing mitochondrial biogenesis; also, it antagonizes ATP loss after hypoxia/reperfusion. Interestingly, GRK2 is able to localize in the mitochondrial outer membrane, possibly through one region within the RGS homology domain and one region within the catalytic domain. In vivo, GRK2 removal from the skeletal muscle results in reduced ATP production and impaired tolerance to ischemia. Our data show a novel sub-cellular localization of GRK2 in the mitochondria and an unexpected role in regulating mitochondrial biogenesis and ATP generation.

Abstract-␤ 2 -Adrenergic receptors (␤ 2 ARs) are widely expressed, although their physiological relevance in many tissuesis not yet fully understood. In vascular endothelial cells, they regulate NO release and vessel tone. Here we provide novel evidence that ␤ 2 ARs can regulate neoangiogenesis in response to chronic ischemia. We used in vivo adenoviral-mediated gene transfer of the human ␤ 2 AR to the endothelium of the rat femoral artery and increased ␤ 2 AR signaling resulting in ameliorated angiographic blood flow and hindlimb perfusion after chronic ischemia. Histological analysis confirmed that ␤ 2 AR overexpression also produced benefits on capillary density. The same maneuver partially rescued impaired angiogenesis in spontaneously hypertensive rats (SHR), whereas gene delivery of the G-proteincoupling defective mutant Ile164 ␤ 2 AR failed to provide ameliorations. Stimulation of endogenous and overexpressed ␤ 2 AR on endothelial cells in vitro was found to regulate cell number by inducing proliferation and [ 3 H]-thymidine incorporation through means of extracellular receptor-activated kinase and vascular endothelial growth factor. The ␤ 2 AR also has novel effects on endothelial cell number through stimulation of proapoptosis and antiapoptosis pathways involving p38 mitogen-activated protein kinase and PI3-kinase/Akt activation. Therefore, ␤ 2 ARs play a critical role in endothelial cell proliferation and function including revascularization, suggesting a novel and physiologically relevant role in neoangiogenesis in response to ischemia. Key Words: angiogenesis Ⅲ rats Ⅲ polymorphism Ⅲ hypertension Ⅲ in vivo digital angiography T he endothelium controls several vascular functions, including vascular tone and permeability, thrombosis, hemostasis, and angiogenesis. 1 It is noteworthy that all these functions can be regulated by activation of receptors, and often, the same receptor can activate multiple endothelial functions.Adult angiogenesis only occurs in particular conditions such as wound healing, tumorogenesis, hypoxia, and chronic ischemia. 2 It is a phenomenon intimately associated with endothelial cell (EC) proliferation, which appears to be under control of the extracellular receptor-activated kinase (ERK)/ mitogen-activated protein kinase (MAPK)-mediated signaling cascades. 2 The most important system regulating angiogenesis is the cytokine vascular endothelial growth factor (VEGF), although a number of other cytokines and hormones acting through various tyrosine kinase and G-protein-coupled receptors are also implicated in this process.The adrenergic system is the major regulator of cardiac and vascular function, and evidence is mounting for the relevance of this system in the control of endothelial vasodilation through means of ␣ 2-and ␤-adrenergic receptors (␤ARs). In particular, ␤ 2 ARs, the most abundant ␤ARs in the vasculature, 3,4 modulate the release of NO, causing endotheliumdependent vasodilation. 5 ␤ 2 ARs are G-protein-coupled receptors activated by adrenergic catecholamines and prom...