Decreased expression of β1- and β2-adrenoceptors in human diabetic atrial appendage

Dinçer, Ü. Deniz; Güner, Şahika; Tay, Aydin; Arıoglu, Ebru; Taşdelen, Atılay; Aşlamacı, Sait; Bidasee, Keshore R.

doi:10.1186/1475-2840-2-6

Cited by 11 publications

(9 citation statements)

References 25 publications

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“…Consequently the non-responsiveness to β-adrenergic stimulation in the isolated right atrial cardiac muscles in our study should reside within the myocardium. Thirdly, although a reduced expression of β 1 -adrenoreceptors has been reported in myocardial tissue from diabetic patients undergoing CABG in the absence of β-blockers [ 37 ], to the best of our knowledge expression of β 1 -adrenoreceptors has never been reported in human myocardial tissue from diabetic patients with preserved EF. Interestingly, we did not observe a statistically significant reduction in β 1 -adrenoreceptors expression levels (Figure 3 F) in the cardiac tissue from our diabetic cohort.…”

Section: Discussionmentioning

confidence: 99%

Impaired relaxation despite upregulated calcium-handling protein atrial myocardium from type 2 diabetic patients with preserved ejection fraction

Lamberts

Lingam

Wang

et al. 2014

Cardiovasc Diabetol

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BackgroundDiastolic dysfunction is a key factor in the development and pathology of cardiac dysfunction in diabetes, however the exact underlying mechanism remains unknown, especially in humans. We aimed to measure contraction, relaxation, expression of calcium-handling proteins and fibrosis in myocardium of diabetic patients with preserved systolic function.MethodsRight atrial appendages from patients with type 2 diabetes mellitus (DM, n = 20) and non-diabetic patients (non-DM, n = 36), all with preserved ejection fraction and undergoing coronary artery bypass grafting (CABG), were collected. From appendages, small cardiac muscles, trabeculae, were isolated to measure basal and β-adrenergic stimulated myocardial function. Expression levels of calcium-handling proteins, sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) and phospholamban (PLB), and of β1-adrenoreceptors were determined in tissue samples by Western blot. Collagen deposition was determined by picro-sirius red staining.ResultsIn trabeculae from diabetic samples, contractile function was preserved, but relaxation was prolonged (Tau: 74 ± 13 ms vs. 93 ± 16 ms, non-DM vs. DM, p = 0.03). The expression of SERCA2a was increased in diabetic myocardial tissue (0.75 ± 0.09 vs. 1.23 ± 0.15, non-DM vs. DM, p = 0.007), whereas its endogenous inhibitor PLB was reduced (2.21 ± 0.45 vs. 0.42 ± 0.11, non-DM vs. DM, p = 0.01). Collagen deposition was increased in diabetic samples. Moreover, trabeculae from diabetic patients were unresponsive to β-adrenergic stimulation, despite no change in β1-adrenoreceptor expression levels.ConclusionsHuman type 2 diabetic atrial myocardium showed increased fibrosis without systolic dysfunction but with impaired relaxation, especially during β-adrenergic challenge. Interestingly, changes in calcium-handling protein expression suggests accelerated active calcium re-uptake, thus improved relaxation, indicating a compensatory calcium-handling mechanism in diabetes in an attempt to maintain diastolic function at rest despite impaired relaxation in the diabetic fibrotic atrial myocardium. Our study addresses important aspects of the underlying mechanisms of diabetes-associated diastolic dysfunction, which is crucial to developing new therapeutic treatments.

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Section: Discussionmentioning

confidence: 99%

Impaired relaxation despite upregulated calcium-handling protein atrial myocardium from type 2 diabetic patients with preserved ejection fraction

Lamberts

Lingam

Wang

et al. 2014

Cardiovasc Diabetol

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“…A persistent hypercat-echolaminergic state, which is seen in high cardiometabolic risk subjects, triggers reversible or irreversible protein modifications in cell surface receptors. Both β 1 and β 2 subtypes have been shown to functionally coexist in the human heart 13–16. The hazardous effects of elevated catecholamine levels are found to be mediated primarily by β 1 -ARs contrary to β 2 -ARs stimulation, which may be adaptive in some cases 13,15,16.…”

Section: Discussionmentioning

confidence: 99%

“…Both β 1 and β 2 subtypes have been shown to functionally coexist in the human heart 13–16. The hazardous effects of elevated catecholamine levels are found to be mediated primarily by β 1 -ARs contrary to β 2 -ARs stimulation, which may be adaptive in some cases 13,15,16. β 1 - and β 2 -ARs each couple to G s ; however, a growing body of recent evidence suggests that β 2 -ARs also couple to inhibitory protein G i 10,12.…”

Section: Discussionmentioning

confidence: 99%

“…β 1 - and β 2 -ARs each couple to G s ; however, a growing body of recent evidence suggests that β 2 -ARs also couple to inhibitory protein G i 10,12. In spite of these differences, the author and colleagues have previously demonstrated that both β 1 - and β 2 -AR expression and β 1 - and β 2 -AR-mediated inotropic and chronotropic responses were decreased in chronic diabetic hearts 13–16. There are a number of explanations for decreased β-AR expression in metabolic syndrome.…”

Section: Discussionmentioning

confidence: 99%

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Cardiac ß-adrenoceptor expression is markedly depressed in Ossabaw swine model of cardiometabolic risk

2011

IJGM

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Ossabaw swine have a “thrifty genotype” and consumption of excess calories induces many classical components of the metabolic syndrome, including obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, hyperleptinemia, and hypertension. Earlier studies indicate that the metabolic syndrome is associated with diminished cardiac function; however, to what degree this impairment is associated with alterations in myocardial β1- and β2-adrenoceptor (AR) expression has not been fully elucidated. Accordingly, the present study was designed to investigate the effects of the metabolic syndrome on cardiac β1- and β2-AR expression. Studies were conducted on left ventricular tissue samples obtained from control lean and chronically (50 weeks) high-fat-fed obese animals. Chronic feeding significantly increased fasting plasma insulin, total cholesterol, triglycerides, blood glucose, systolic and diastolic blood pressure, and heart rate. Real-time polymerase chain reaction revealed no significant alterations in cardiac β1- and β2-AR mRNA expression. In contrast, Western blot analysis revealed a significant decrease in ventricular β1- and β2-AR protein expression. This is the first report in a novel large animal model that induction of metabolic syndrome is accompanied by a significant reduction in cardiac β1- and β2-AR protein expression that could contribute to impaired cardiac function.

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“…β-AR activation augments calcium uptake and increases sarcoendoplasmic reticulum activity by upregulating sarcoendoplasmic reticulum ATPase-2a (SERCA-2a), which increases contractility of the cardiomyocytes (18). In diabetic hearts, SERCA-2a is decreased (18), and β 1 -AR and β 2 -AR are downregulated (19). …”

Section: Introductionmentioning

confidence: 99%

Lack of miR-133a Decreases Contractility of Diabetic Hearts: A Role for Novel Cross Talk Between Tyrosine Aminotransferase and Tyrosine Hydroxylase

et al. 2016

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MicroRNAs (miRNAs) have a fundamental role in diabetic heart failure. The cardioprotective miRNA-133a (miR-133a) is downregulated, and contractility is decreased in diabetic hearts. Norepinephrine (NE) is a key catecholamine that stimulates contractility by activating β-adrenergic receptors (β-AR). NE is synthesized from tyrosine by the rate-limiting enzyme, tyrosine hydroxylase (TH), and tyrosine is catabolized by tyrosine aminotransferase (TAT). However, the cross talk/link between TAT and TH in the heart is unclear. To determine whether miR-133a plays a role in the cross talk between TH and TAT and regulates contractility by influencing NE biosynthesis and/or β-AR levels in diabetic hearts, Sprague-Dawley rats and miR-133a transgenic (miR-133aTg) mice were injected with streptozotocin to induce diabetes. The diabetic rats were then treated with miR-133a mimic or scrambled miRNA. Our results revealed that miR-133a mimic treatment improved the contractility of the diabetic rat’s heart concomitant with upregulation of TH, cardiac NE, β-AR, and downregulation of TAT and plasma levels of NE. In miR-133aTg mice, cardiac-specific miR-133a overexpression prevented upregulation of TAT and suppression of TH in the heart after streptozotocin was administered. Moreover, miR-133a overexpression in CATH.a neuronal cells suppressed TAT with concomitant upregulation of TH, whereas knockdown and overexpression of TAT demonstrated that TAT inhibited TH. Luciferase reporter assay confirmed that miR-133a targets TAT. In conclusion, miR-133a controls the contractility of diabetic hearts by targeting TAT, regulating NE biosynthesis, and consequently, β-AR and cardiac function.

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Decreased expression of β1- and β2-adrenoceptors in human diabetic atrial appendage

Cited by 11 publications

References 25 publications

Impaired relaxation despite upregulated calcium-handling protein atrial myocardium from type 2 diabetic patients with preserved ejection fraction

Impaired relaxation despite upregulated calcium-handling protein atrial myocardium from type 2 diabetic patients with preserved ejection fraction

Cardiac ß-adrenoceptor expression is markedly depressed in Ossabaw swine model of cardiometabolic risk

Lack of miR-133a Decreases Contractility of Diabetic Hearts: A Role for Novel Cross Talk Between Tyrosine Aminotransferase and Tyrosine Hydroxylase

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Decreased expression of β1- and β2-adrenoceptors in human diabetic atrial appendage

Cited by 11 publications

References 25 publications

Impaired relaxation despite upregulated calcium-handling protein atrial myocardium from type 2 diabetic patients with preserved ejection fraction

Impaired relaxation despite upregulated calcium-handling protein atrial myocardium from type 2 diabetic patients with preserved ejection fraction

Cardiac &szlig;-adrenoceptor expression is markedly depressed in Ossabaw swine model of cardiometabolic risk

Lack of miR-133a Decreases Contractility of Diabetic Hearts: A Role for Novel Cross Talk Between Tyrosine Aminotransferase and Tyrosine Hydroxylase

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Cardiac ß-adrenoceptor expression is markedly depressed in Ossabaw swine model of cardiometabolic risk