Ischemic Inactivation of G Protein–Coupled Receptor Kinase and Altered Desensitization of Canine Cardiac β-Adrenergic Receptors

Yu, Xichun; Zhang, Min; Kyker, Kimberly D.; Patterson, Eugene; Benovic, Jeffrey L.; Kem, David C.

doi:10.1161/01.cir.102.20.2535

Cited by 26 publications

(30 citation statements)

References 33 publications

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“…This corresponds with the fact that in the ischemic tissue there is a loss of the ability to desensitize to β-AR stimulation 24 h after CAL. This is in temporal correspondence with a second peak in sudden cardiac death observed between 6 h and 24 h in dog and rat models of MI [30]. Raake et al…”

Section: G Protein Related Kinases -General Overviewsupporting

confidence: 75%

“…This period roughly coincides with an observed second peak for susceptibility and development of β-AR-sensitive ventricular arrhythmias and sudden cardiac death in animal models [30]. GRK-2, but not GRK-5, activity in the sub-epicardial border zone was reduced 24 h after CAL compared with the non-ischemic subepicardial tissue [30]. This corresponds with the fact that in the ischemic tissue there is a loss of the ability to desensitize to β-AR stimulation 24 h after CAL.…”

Section: G Protein Related Kinases -General Overviewsupporting

confidence: 75%

“…There are few studies of β-AR transduction sensitivity in animal models of MI during the sub-acute period extending from 6 h to 24 h after CAL [30,31]. This period roughly coincides with an observed second peak for susceptibility and development of β-AR-sensitive ventricular arrhythmias and sudden cardiac death in animal models [30]. GRK-2, but not GRK-5, activity in the sub-epicardial border zone was reduced 24 h after CAL compared with the non-ischemic subepicardial tissue [30].…”

Section: G Protein Related Kinases -General Overviewmentioning

confidence: 99%

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

Bojić¹,

Sudar-Milovanović²,

Mikhailidis³

et al. 2012

aoms

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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: :

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Section: G Protein Related Kinases -General Overviewsupporting

confidence: 75%

Section: G Protein Related Kinases -General Overviewsupporting

confidence: 75%

Section: G Protein Related Kinases -General Overviewmentioning

confidence: 99%

See 1 more Smart Citation

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

Bojić¹,

Sudar-Milovanović²,

Mikhailidis³

et al. 2012

aoms

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“…To determine whether the rapid decrease in GRK2 following myocardial ischemia, as shown both by immunoblot (33,34) and in the present study by immunofluorescence microscopy, represents a transcriptional downregulation or a posttranscriptional event, we used quantitative real-time RT-PCR to compare GRK2 and GRK5 mRNA levels in the ischemic and control tissues. Although there was a numerical increase in GRK2 mRNA, normalized to levels of GAPDH mRNA, in the EBZ and infarct tissues (Fig.…”

Section: D-f)mentioning

confidence: 95%

“…In the dog, the late arrhythmias represent primarily sustained reentrant tachycardia from the subepicardial border zone tissue (EBZ). We have reported a marked decrease in total GRK2 activity in whole slices of canine EBZ tissue obtained during the subacute period 6 -24 period after infarction, resulting in a loss of the ability of the EBZ tissue to become desensitized to ␤-adrenergic stimulation (33,34). This heightened sensitivity predisposes this tissue to ␤-agonist-induced ventricular tachyarrhythmias and provides a biochemical rationale for the effectiveness of ␤-blockers in preventing SCD.…”

mentioning

confidence: 98%

Proteasome degradation of GRK2 during ischemia and ventricular tachyarrhythmias in a canine model of myocardial infarction

Yu¹,

Huang²,

Patterson³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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Arrhythmia-prone subepicardial border zone (EBZ) tissue demonstrates decreased G protein receptor kinase 2 (GRK2) activity and increased sensitivity to isoproterenol 6 -24 h after coronary artery ligation (CAL) in the dog. With the use of a semiquantitative immunofluorescence technique, the relative fluorescence intensity (RF) of GRK2 in EBZ decreased to 24% of that in a remote site (RS) (P Ͻ 0.01, n ϭ 30 cells from 3 dogs), whereas GRK5 RF did not change. Confocal studies of cardiac tissue from transgenic mice overexpressing GRK2 validated the use of a semilogarithmic relationship between RF and GRK2 activity. As shown with the use of quantitative real-time RT-PCR, both GRK2 and GRK5 mRNA were not decreased at 24 h in EBZ (n ϭ 6 dogs) relative to RS control, indicating that the decrease of GRK2 in the EBZ is likely due to posttranscriptional degradation following CAL. Pretreatment of six dogs with the selective proteasome inhibitor bortezomib provided 100% (EBZ) and 50% (infarct) protection against loss of GRK2 at 24 h. There was an absence of rapid (Ͼ300 beats/min) and very rapid (Ͼ360 beats/min) ventricular triplets that are highly predictive of sudden cardiac death during ECG monitoring in the bortezomib-pretreated animals in contrast to nonpretreated infarcted animals. We have demonstrated that the dramatic decrease in GRK2 in cardiac ischemic tissue can be largely blocked by prior proteasome blockade and that this is associated with significant cardioprotection against malignant ventricular tachyarrhythmias.

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Transient Hypoxia Differentially Decreases GRK2 Protein Levels in CHO Cells Stably Expressing the m1 mAChR

Mou

Jackson

2001

Biochemical and Biophysical Research Communications

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Ischemic Inactivation of G Protein–Coupled Receptor Kinase and Altered Desensitization of Canine Cardiac β-Adrenergic Receptors

Cited by 26 publications

References 33 publications

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

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

Proteasome degradation of GRK2 during ischemia and ventricular tachyarrhythmias in a canine model of myocardial infarction

Transient Hypoxia Differentially Decreases GRK2 Protein Levels in CHO Cells Stably Expressing the m1 mAChR

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