G-protein-coupled receptor kinase activity is increased in hypertension.

Gros, Robert; Benovic, Jeffrey L.; Tan, Christopher M.; Feldman, Ross D.

doi:10.1172/jci119381

Cited by 207 publications

(165 citation statements)

References 34 publications

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“…The important role of increased cardiac ␤-ARK in the pathophysiology of ␤-AR signaling has been consolidated in animal and human models of heart failure (29). At the vascular level, increased ␤-ARK protein expression was demonstrated in spontaneously hypertensive rats, suggesting that increased ␤-ARK activity might account for the impairment of ␤-AR-mediated vasodilation observed in hypertension (13,14). Consistent with this, a recent report showed impaired ␤-AR vasorelaxation and hypertension in transgenic mice with selective overexpression of ␤-ARK in vascular smooth muscle cells (10).…”

Section: Discussionmentioning

confidence: 99%

“…During the past years, the implications of impaired ␤-AR signaling in the pathophysiology of several cardiovascular disorders were explored in animals as well as in humans. Data from these studies indicate that changes in ␤-AR function are associated with heart failure (6,38), hypertension (13,14), and hypertension complicated with ventricular hypertrophy (2).…”

mentioning

confidence: 99%

“…In the failing human heart the uncoupling of cardiac ␤ 1 -and ␤ 2 -ARs from G proteins has been attributed to increased levels of myocardial ␤-ARK (38). Abnormalities of ␤-AR signaling due to increase in ␤-ARK activity have been observed in both human (14) and animal (10,13) hypertension.…”

mentioning

confidence: 99%

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Exercise restores β-adrenergic vasorelaxation in aged rat carotid arteries

Leosco

Iaccarino

Cipolletta

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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Aging is associated with alterations in β-adrenergic receptor (β-AR) signaling and reduction in cardiovascular responses to β-AR stimulation. Because exercise can attenuate age-related impairment in myocardial β-AR signaling and function, we tested whether training could also exert favorable effects on vascular β-AR responses. We evaluated common carotid artery responsiveness in isolated vessel ring preparations from 8 aged male Wistar-Kyoto (WKY) rats trained for 6 wk in a 5 days/wk swimming protocol, 10 untrained age-matched rats, and 10 young WKY rats. Vessels were preconstricted with phenylephrine (10-6 M), and vasodilation was assessed in response to the β-AR agonist isoproterenol (10-10-3 × 10-8 M), the α2-AR agonist UK-14304 (10-9-10-6 M), the muscarinic receptor agonist ACh (10-9-10-6 M), and nitroprusside (10-8-10-5 M). β-AR density and cytoplasmic β-AR kinase (β-ARK) activity were tested on pooled carotid arteries. β-ARK expression was assessed in two endothelial cell lines from bovine aorta and aorta isolated from a 12-wk WKY rat. β-AR, α2-AR, and muscarinic responses, but not that to nitroprusside, were depressed in untrained aged vs. young animals. Exercise training restored β-AR and muscarinic responses but did not affect vasodilation induced by UK-14304 and nitroprusside. Aged carotid arteries showed reduced β-AR number and increased β-ARK activity. Training counterbalanced these phenomena and restored β-AR density and β-ARK activity to levels observed in young rat carotids. Our data indicate that age impairs β-AR vasorelaxation in rat carotid arteries through β-AR downregulation and desensitization. Exercise restores this response and reverts age-related modification in β-ARs and β-ARK. Our data support an important role for β-ARK in vascular β-AR vasorelaxation.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Exercise restores β-adrenergic vasorelaxation in aged rat carotid arteries

Leosco

Iaccarino

Cipolletta

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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“…GRK2 expression and activity are increased in lymphocytes from patients with essential hypertension (26) and genetically hypertensive rats (27). However, the increase in GRK2 expression and activity in the spontaneously hypertensive rat followed the development of hypertension (27).…”

mentioning

confidence: 99%

G protein-coupled receptor kinase 4 gene variants in human essential hypertension

Felder

Sanada

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

249

419

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Essential hypertension has a heritability as high as 30 -50%, but its genetic cause(s) has not been determined despite intensive investigation. The renal dopaminergic system exerts a pivotal role in maintaining fluid and electrolyte balance and participates in the pathogenesis of genetic hypertension. In genetic hypertension, the ability of dopamine and D1-like agonists to increase urinary sodium excretion is impaired. A defective coupling between the D1 dopamine receptor and the G protein͞effector enzyme complex in the proximal tubule of the kidney is the cause of the impaired renal dopaminergic action in genetic rodent and human essential hypertension. We now report that, in human essential hypertension, single nucleotide polymorphisms of a G protein-coupled receptor kinase, GRK4␥, increase G protein-coupled receptor kinase (GRK) activity and cause the serine phosphorylation and uncoupling of the D1 receptor from its G protein͞effector enzyme complex in the renal proximal tubule and in transfected Chinese hamster ovary cells. Moreover, expressing GRK4␥A142V but not the wild-type gene in transgenic mice produces hypertension and impairs the diuretic and natriuretic but not the hypotensive effects of D1-like agonist stimulation. These findings provide a mechanism for the D1 receptor coupling defect in the kidney and may explain the inability of the kidney to properly excrete sodium in genetic hypertension.L ong-term regulation of blood pressure is vested in the organ responsible for the control of body fluid volume, the kidney (1, 2). Dopamine facilitates the antihypertensive function of the kidney because it is both vasodilatory and natriuretic (3). Dopamine (produced by renal proximal tubules) via D 1 -like receptors is responsible for over 50% of incremental sodium excretion when sodium intake is increased (3-6). The paracrine͞ autocrine dopaminergic regulation of sodium excretion is mediated by tubular but not by hemodynamic mechanisms (6). The ability of dopamine and D 1 -like agonists to decrease renal proximal tubular sodium reabsorption is impaired in genetic rodent hypertension and human essential hypertension (3,5,(7)(8)(9)(10)(11)(12)(13)(14)(15). Indeed, the aberrant D 1 -like receptor function in the kidney precedes and cosegregates with high blood pressure in spontaneously hypertensive rats. In addition, disruption of the D 1 receptor in mice produces hypertension (12, 13). The pivotal role of dopamine in the excretion of sodium after increased sodium intake has led to the hypothesis that an aberrant renal dopaminergic system is important in the pathogenesis of some forms of genetic hypertension (3,5,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Several mechanisms potentially responsible for the failure of endogenous renal dopamine to engender a natriuretic effect in genetic hypertension have been investigated and ruled out, including decreased renal dopamine production and receptor expression, aberrant nephron segment distribution of dopamine receptors, defective effector enzymes (adenylyl cyclase or...

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“…10,17 Indeed, it is upregulated in patients with HF and it has also been observed in several animal models. 10,[18][19][20][21] Moreover, enhanced GRK2 expression has been linked to hypertension, 22 cardiac hypertrophy 23 and postmyocardial infarction (MI). 24 In consideration of the fact that GRK2 levels often increase before manifested clinical HF, 25 and normalize again with advanced b-adrenergic signaling and ventricular function, 26,27 GRK2 not only represents a potential biomarker of cardiac function, 28 but is also an attractive therapeutic target for HF treatment.…”

Section: Grk2: a Nodal Culprit In Hf Grk2 And The Cardiomyocytementioning

confidence: 99%

Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade

et al. 2012

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Heart failure (HF) is a common pathological end point for several cardiac diseases. Despite reasonable achievements in pharmacological, electrophysiological and surgical treatments, prognosis for chronic HF remains poor. Modern therapies are generally symptom oriented and do not currently address specific intracellular molecular signaling abnormalities. Therefore, new and innovative therapeutic approaches are warranted and, ideally, these could at least complement established therapeutic options if not replace them. Gene therapy has potential to serve in this regard in HF as vectors can be directed toward diseased myocytes and directly target intracellular signaling abnormalities. Within this review, we will dissect the adrenergic system contributing to HF development and progression with special emphasis on G-protein-coupled receptor kinase 2 (GRK2). The levels and activity of GRK2 are increased in HF and we and others have demonstrated that this kinase is a major molecular culprit in HF. We will cover the evidence supporting gene therapy directed against myocardial as well as adrenal GRK2 to improve the function and structure of the failing heart and how these strategies may offer complementary and synergistic effects with the existing HF mainstay therapy of b-adrenergic receptor antagonism.

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G-protein-coupled receptor kinase activity is increased in hypertension.

Cited by 207 publications

References 34 publications

Exercise restores β-adrenergic vasorelaxation in aged rat carotid arteries

Exercise restores β-adrenergic vasorelaxation in aged rat carotid arteries

G protein-coupled receptor kinase 4 gene variants in human essential hypertension

Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade

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