The Effect of Diabetes on Expression of β1-,β2-, and β3-Adrenoreceptors in Rat Hearts

Dinçer, Ü. Deniz; Bidasee, Keshore R.; Güner, Şahika; Tay, Ayin; Özçeli̇kay, A.Tanju; Altan, V.Melih

doi:10.2337/diabetes.50.2.455

Cited by 161 publications

(180 citation statements)

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“…The ␤-adrenergic pathway is desensitized in diabetes, both in patients and animal models, and receptor changes are often considered a primary cause (14). However, cardiomyocytes isolated from STZ-induced diabetic animals show contractile impairment upon activation of ␤-adrenergic receptors, adenylate cyclase, or PKA (15,16).…”

Section: Discussionmentioning

confidence: 99%

“…In diabetes, this is partly from a reduction in ␤ 1 -adrenergic receptor content and function (14); however adrenergic impairment in the diabetic heart is likely more complex. For example, cardiomyocytes isolated from diabetic animals maintain a blunted response to adenylate cyclase and PKA agonists despite these drugs bypassing the receptor and cAMP production (15,16).…”

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confidence: 99%

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cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart

Humphries

2015

Journal of Biological Chemistry

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Diabetes mellitus causes cardiac dysfunction and heart failure that is associated with metabolic abnormalities and autonomic impairment. Autonomic control of ventricular function occurs through regulation of cAMP-dependent protein kinase (PKA). The diabetic heart has suppressed ␤-adrenergic responsiveness, partly attributable to receptor changes, yet little is known about how PKA signaling is directly affected. Control and streptozotocin-induced diabetic mice were therefore administered 8-bromo-cAMP (8Br-cAMP) acutely to activate PKA in a receptorindependent manner, and cardiac hemodynamic function and PKA signaling were evaluated. In response to 8Br-cAMP treatment, diabetic mice had impaired inotropic and lusitropic responses, thus demonstrating postreceptor defects. This impaired signaling was mediated by reduced PKA activity and PKA catalytic subunit content in the cytoplasm and myofilaments. Compartment-specific loss of PKA was reflected by reduced phosphorylation of discrete substrates. In response to 8Br-cAMP treatment, the glycolytic activator PFK-2 was robustly phosphorylated in control animals but not diabetics. Control adult cardiomyocytes cultured in lipid-supplemented media developed similar changes in PKA signaling, suggesting that lipotoxicity is a contributor to diabetes-induced ␤-adrenergic signaling dysfunction. This work demonstrates that PKA signaling is impaired in diabetes and suggests that treating hyperlipidemia is vital for proper cardiac signaling and function.Diabetes mellitus carries at least twice the risk of cardiovascular complications such as coronary artery disease, hypertension, and heart failure (1, 2). Diabetes can directly cause heart failure, in the case of diabetic cardiomyopathy, as well as exacerbate other comorbidities (3, 4). The reasons for this are multifaceted and involve both metabolic and mechanical cardiac stresses. Metabolic abnormalities include metabolic inflexibility caused by improper glucose uptake and oxidation and by lipotoxicity induced by lipid overload (5). Diabetes, in common with other forms of heart failure, has impairment of autonomic control and overstimulation of the sympathetic nervous system (6, 7). The etiology of chronic cardiac stimulation in diabetes is characterized by sympathetic enhancement and parasympathetic withdrawal (3, 8). Excess sympathetic stimulation over time causes extensive dysfunction to the ␤-adrenergic pathway, a process that is intimately tied with heart failure (9, 10).Normally, ligand binding to ␤ 1 -receptors activates G s proteins, which stimulate adenylate cyclase to produce cAMP. The primary target of cAMP is cAMP-dependent protein kinase (PKA), 2 a heterotetrameric protein comprised of two catalytic (PKA-C) and two regulatory subunits (either PKA-RI or PKA-RII isoforms). cAMP binds PKA-R subunits and induces the release of PKA-C, which then phosphorylates specific serines and threonines on protein targets in the cytoplasm, myofilaments, sarcoplasmic reticulum, sarcolemma, and nucleus to increase cardiac output, metab...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart

Humphries

2015

Journal of Biological Chemistry

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“…At the same time, the functioning of adrenergic signaling system in type 1 DM differs from that in type 2 DM. In animals with streptozotocin insulindeficient DM some authors have revealed redistribution of the b-adrenoceptors [41][42][43] and weakening of their functional activity [44,45], whereas others have found no changes in their functional activity [46][47][48]. Despite a decreased density of b-adrenoceptors in the myocardial membranes from rats and swine with type 1 DM, there are no differences in the number of high-affinity b-adrenoceptors, neither in the ability of isoproterenol to stimulate AC activity in diabetic and non-diabetic animals [46,47].…”

Section: Discussionmentioning

confidence: 99%

Intranasal insulin affects adenyl cyclase system in rat tissues in neonatal diabetes

Chistyakova

Derkach

et al. 2011

Open Life Sciences

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Intranasal insulin affects adenyl cyclase system in rat tissues in neonatal diabetes Abbreviations:AC -adenylyl cyclase; AC system -adenylyl cyclase signaling system; DM -diabetes mellitus; EMD-386088 -5 -c h l o r o -2 -m e t h y l -3 -( 1 , 2 , 3 , 6 -tetrahydro-4-pyridinyl)-1H-indole; GppNHp -b,g-imidoguanosine-5'-triphosphate; 5-HT receptor -5-hydroxytryptamine receptor; hCG -human chorionic gonadotropin; PACAP-38 -pituitary adenylyl cyclase-activating peptide-38. IntroductionHypertension, coronary heart diseases, atherosclerosis, nephropathy, retinopathy, neuropathy, cognitive deficit and disorders of the reproductive system are the most common complications of diabetes mellitus (DM) [1][2][3]. Chronic hyperglycemia is quite often an important contributing factor in the development of these complications. Many hormone-and growth factorregulated signaling pathways, such as the adenylyl cyclase (AC) signaling system, phospholipase C/protein kinase C signaling system and the cascade of mitogenactivated protein kinases are implicated in the regulation of the cardiovascular, nervous and reproductive systems and aberration of their functional activity in DM may contribute to complications of this disease [4][5][6][7][8]. It has been shown that in experimental types 1 and 2 DM the functional activity of hormone-sensitive AC system in the skeletal muscles, myocardium, testis, ovaries, uterus and brain of diabetic rats and the sensitivity of this system to hormones regulating AC activity are changed in tissue-and hormone-specific manner [6][7][8][9][10][11][12].The most significant changes of hormonal sensitivity of AC system were found in the myocardium, testis and Abstract:The changes in hormone-regulated adenylyl cyclase (AC) signaling system implicated in control of the nervous, cardiovascular and reproductive systems may contribute to complications of diabetes mellitus (DM). We investigated the functional state of AC system in the brain, myocardium, ovary and uterus of rats with neonatal DM and examined the influence of intranasally administered insulin on the sensitivity of this system to biogenic amines and polypeptide hormones. The regulatory effects of somatostatin and 5-HT 1B R-agonist 5-nonyloxytryptamine acting via G i protein-coupled receptors were significantly decreased in DM and partially restored in insulin-treated rats. The effects of hormones, activators of AC, are changed in tissue-and receptorspecific manner, and intranasal insulin restored the effects rather close to the level in control. In insulin-treated non-diabetic rats, AC stimulating effects of isoproterenol and relaxin in the myocardium and of human chorionic gonadotropin in the ovaries were decreased, while the effects of hormones, inhibitors of AC, were increased. These data indicate that with intranasal insulin, G i protein-mediated signaling pathways continue to gain strength. The obtained data on the influence of hormones on AC system in the brain, myocardium, ovary and uterus allow looking anew into the mechanisms of therapeutic ...

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“…5 An upregulation of beta3-AR also was observed in human hearts with ischemic or dilated cardiomyopathy, 6 in the failing canine myocardium, 3 and in hearts of long-term diabetic rats. 7 Whether or not the upregulation of beta3-AR is merely in response to excess catecholamines or confer additional risk or benefit for arrhythmia is unclear. Beta3-AR was suggested to function as a buffer against excessive beta1-AR and beta2-AR stimulation in disease conditions associated with hyperadrenergic activity, such as heart failure.…”

Section: Introductionmentioning

confidence: 99%