Enhanced GRK2 Expression and Desensitization of βAR Vasodilatation in Hypertensive Patients

Izzo, Raffaele; Cipolletta, Ersilia; Ciccarelli, Michele; Campanile, Alfonso; Santulli, Gaetano; Palumbo, Gianluigi; Vasta, Antonio; Formisano, S; Trimarco, Bruno; Iaccarino, Guido

doi:10.1111/j.1752-8062.2008.00050.x

Cited by 64 publications

(64 citation statements)

References 33 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, GRK2 levels are increased in young patients with hypertension compared with both normotensively young and old patients (92). In agreement are the studies in hypertensive patients showing increased peripheral blood lymphocyte GRK2 levels (116). Overall, increased GRK2 levels are correlated with increased blood pressure (94).…”

Section: Grk2 and Hypertensionsupporting

confidence: 68%

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

Sato

Chuprun

Schwartz

et al. 2015

Physiological Reviews

126

152

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) are important regulators of various cellular functions via activation of intracellular signaling events. Active GPCR signaling is shut down by GPCR kinases (GRKs) and subsequent β-arrestin-mediated mechanisms including phosphorylation, internalization, and either receptor degradation or resensitization. The seven-member GRK family varies in their structural composition, cellular localization, function, and mechanism of action (see sect. II). Here, we focus our attention on GRKs in particular canonical and novel roles of the GRKs found in the cardiovascular system (see sects. III and IV). Paramount to overall cardiac function is GPCR-mediated signaling provided by the adrenergic system. Overstimulation of the adrenergic system has been highly implicated in various etiologies of cardiovascular disease including hypertension and heart failure. GRKs acting downstream of heightened adrenergic signaling appear to be key players in cardiac homeostasis and disease progression, and herein we review the current data on GRKs related to cardiac disease and discuss their potential in the development of novel therapeutic strategies in cardiac diseases including heart failure.

show abstract

Section: Grk2 and Hypertensionsupporting

confidence: 68%

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

Sato

Chuprun

Schwartz

et al. 2015

Physiological Reviews

126

152

View full text Add to dashboard Cite

show abstract

“…These data imply that the primary abnormality of β-AR signaling pathway is GRK-2 overexpression in vascular smooth muscle causing β-AR desensitization and decreased vasodilatation [57]. Also, the desensitization of β-ARs and an increase in GRK-2 is confirmed in hypertensive patients [52,58]. Although GRK-2 polymorphisms have not been associated with essential hypertension [59], increased GRK-2 expression (but not GRK-5) has been reported in lymphocytes of African Americans with hypertension, where hypertension occurs with higher prevalence and morbidity [60].…”

Section: H Hy Yp Pe Er Rt Te En Ns Si Io On Nsupporting

confidence: 48%

“…These data support the fact that GRK-2 is important in the development of post-MI and HF. Elevated levels of GRK-2 are present both in human hypertension [52,58] and animal models of hypertension [54,56]. Therefore, the inhibition of GRK may prove to be a therapeutic approach for the treatment of hypertension [57], opening new perspectives for modern hypertension management [79].…”

Section: Therapeutic Implications Of G Protein Related Kinases Molecumentioning

confidence: 99%

“…In hypertension, the balance between α1-AR and β-AR systems is shifted towards vasoconstriction, probably due to the defective vasodilatation in response to β-adrenergic stimulation. β-AR agonist administration in the human brachial artery causes vasodilatation, with this response attenuated in hypertension [49,52]. GRK-2, the enzyme responsible for fast desensitization of β-AR, is abundantly expressed in the heart and vessels [53].…”

Section: H Hy Yp Pe Er Rt Te En Ns Si Io On Nmentioning

confidence: 99%

“…The elevated cardiac output, vascular resistance, and blood pressure at that stage can be fully normalized by autonomic blockade [51]. The release of norepinephrine, the major sympathetic neurotransmitter, at the vascular level induces the activation of α1-AR, which mediates vasoconstriction, and β-ARs, which cause vasodilatation [52]. In hypertension, the balance between α1-AR and β-AR systems is shifted towards vasoconstriction, probably due to the defective vasodilatation in response to β-adrenergic stimulation.…”

Section: H Hy Yp Pe Er Rt Te En Ns Si Io On Nmentioning

confidence: 99%

See 2 more Smart Citations

State of the art paper The role of G protein coupled receptor kinases in neurocardiovascular pathophysiology

Bojić¹,

Sudar-Milovanović²,

Mikhailidis³

et al. 2012

aoms

View full text Add to dashboard Cite

A b s t r a c tIn coronary artery disease the G protein related kinases (GRKs) play a role in desensitization of β-adrenoreceptors (AR) after coronary occlusion. Targeted deletion and lowering of cardiac myocyte GRK-2 decreases the risk of postischemic heart failure (HF). Studies carried out in humans confirm the role of GRK-2 as a marker for the progression of HF after myocardial infarction (MI). The level of GRK-2 could be an indicator of β-AR blocker efficacy in patients with acute coronary syndrome. Elevated levels of GRK-2 are an early ubiquitous consequence of myocardial injury. In hypertension an increased level of GRK-2 was reported in both animal models and human studies. The role of GRKs in vagally mediated disorders such as vasovagal syncope and atrial fibrillation remains controversial. The role of GRKs in the pathogenesis of neurocardiological diseases provides an insight into the molecular pathogenesis process, opens potential therapeutic options and suggests new directions for scientific research.K Ke ey y w wo or rd ds s: : autonomic, sympathetic, vagal, molecular signaling pathway. Neurocardiovascular pathophysiology: sympathetic versus vagally mediated disordersNeural control of the cardiovascular (CV) system is an integral part of CV physiology and consequently a part of CV pathological mechanisms. Two fundamental parts of the autonomic nervous system -the sympathetic and parasympathetic (vagal) components -play a role in the development and initiation of the pathological process. The classification of neurocardiological disorders by Goldstein [1] is as follows: 1) Sympathetic disorders -diseases in which activation of the catecholamine system worsens an independent pathological state (coronary artery disease, arrhythmias as long QT syndrome, sudden death, heart failure (HF)) as well as diseases in which abnormal catecholaminergic function is etiologic (sympathetic neurocirculatory failure, hypertension, cardiac necrosis and cardiomyopathy), and 2) Vagally mediated disorders -both neurally mediated syncope (vasovagal syncope, carotid sinus hypersensitivity) and vagally mediated atrial fibrillation. Neural regulation of the CV system can be studied by using different techniques [2][3][4][5][6][7][8]. G protein related kinases (GRKs) exist in 7 isoforms -GRK 1-7. They are serine-threonine protein kinases that are C Co or rr re es sp po on nd di in ng g a au ut th ho or r: :

show abstract

Dopamine and Renal Function and Blood Pressure Regulation

Armando

Villar

José

2011

Comprehensive Physiology

104

215

View full text Add to dashboard Cite

Dopamine is an important regulator of systemic blood pressure via multiple mechanisms. It affects fluid and electrolyte balance by its actions on renal hemodynamics and epithelial ion and water transport and by regulation of hormones and humoral agents. The kidney synthesizes dopamine from circulating or filtered L-DOPA independently from innervation. The major determinants of the renal tubular synthesis/release of dopamine are probably sodium intake and intracellular sodium. Dopamine exerts its actions via two families of cell surface receptors, D1-like receptors comprising D1R and D5R, and D2-like receptors comprising D2R, D3R, and D4R, and by interactions with other G protein-coupled receptors. D1-like receptors are linked to vasodilation, while the effect of D2-like receptors on the vasculature is variable and probably dependent upon the state of nerve activity. Dopamine secreted into the tubular lumen acts mainly via D1-like receptors in an autocrine/paracrine manner to regulate ion transport in the proximal and distal nephron. These effects are mediated mainly by tubular mechanisms and augmented by hemodynamic mechanisms. The natriuretic effect of D1-like receptors is caused by inhibition of ion transport in the apical and basolateral membranes. D2-like receptors participate in the inhibition of ion transport during conditions of euvolemia and moderate volume expansion. Dopamine also controls ion transport and blood pressure by regulating the production of reactive oxygen species and the inflammatory response. Essential hypertension is associated with abnormalities in dopamine production, receptor number, and/or posttranslational modification.

show abstract

Enhanced GRK2 Expression and Desensitization of βAR Vasodilatation in Hypertensive Patients

Cited by 64 publications

References 33 publications

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

State of the art paper The role of G protein coupled receptor kinases in neurocardiovascular pathophysiology

Dopamine and Renal Function and Blood Pressure Regulation

Contact Info

Product

Resources

About