Noninvasive evaluation of cardiac dysfunction by echocardiography in streptozotocin-induced diabetic rats

Hoit, Brian D.; Castro, C Pablo; Bultron, Gilberto; Knight, S E; Matlib, Mohammed A.

doi:10.1016/s1071-9164(99)91337-4

Cited by 80 publications

(84 citation statements)

References 26 publications

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“…*, p Ͻ 0.05; **, p Ͻ 0.005; ***, p Ͻ 0.0005, unpaired Student's t test except for H, which was analyzed by two-way analysis of variance. functional decreases (13). This suggests that increased sympathetic activity compensates initially and follows other types of heart failure in which increased adrenergic signaling becomes impaired over time (10,32,33).…”

Section: Discussionmentioning

confidence: 97%

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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: 97%

“…Persistent activation of the ␤-adrenergic pathway ultimately leads to a blunted response to additional ligand stimulation (13). 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.…”

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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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“…Cardiac function was not directly assessed in this study, but it is likely that rats with 32 weeks duration of diabetes have cardiac dysfunction, particularly as echocardiographic studies have shown decreased cardiac contractility in this model 29 as early as 6 weeks after the induction of diabetes. 30 Other cardiac abnormalities observed in diabetic rats were increased LV mass and cardiac BNP expression. BNP is released from ventricular myocardium in response to increased wall stress and reflects both systolic and diastolic cardiac dysfunction.…”

Section: Discussionmentioning

confidence: 99%

A Breaker of Advanced Glycation End Products Attenuates Diabetes-Induced Myocardial Structural Changes

Candido

Forbes

Thomas

et al. 2003

Circulation Research

403

287

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“…6 In the development of diabetic cardiomyopathy, DHF can be observed at an early stage, followed by progressive systolic heart failure at a later stage. 9,10 It was suggested that patients with both DM and HT complicate LV diastolic dysfunction more severely than those with either condition alone. 11 Earlier studies have shown that DM exacerbates LV remodeling and heart failure after myocardial infarction in mice, wherein angiotensin II plays an important pathogenetic role.…”

Section: Introductionmentioning

confidence: 99%

Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin–angiotensin system in hypertensive rats

et al. 2009

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Diabetes mellitus (DM) is a major risk factor for heart failure, independent of coronary artery disease or hypertension (HT). Therefore, our study was designed to examine the mechanisms of DM-induced left ventricular (LV) diastolic dysfunction. In this study, we made five different 10-week treatment groups of Dahl salt-sensitive rats as follows: Control; a low-salt (0.5% NaCl) diet, HT; a high-salt (5% NaCl) diet, DM; a low-salt diet with streptozotocin (STZ) injection (30 mg kg À1 i.p.), HT+DM; a highsalt diet with STZ injection, and the Olmesartan group; a high-salt diet with STZ treated with an angiotensin receptor blocker, olmesartan (1 mg kg À1 day À1 ). Cardiac diastolic dysfunction with a preserved systolic function was noted in the HT group, and was most prominently noted in the HT+DM group, characterized by enhanced cardiac fibrosis, whereas the extent of HT and myocardial hypertrophy was comparable between the two groups. Myocardial expressions of collagen III, transforming growth factor-b2, angiotensin-converting enzyme (ACE), angiotensin II type-1 receptor and myocardial oxidative stress (evaluated by 4-hydroxy-2-nonenal-modified protein) were mostly enhanced in the HT+DM group. Importantly, there was a positive correlation between the extent of diastolic dysfunction and that of myocardial ACE expression. All these cardiac abnormalities induced by DM and HT were ameliorated in the olmesartan group. These results indicate that DM accelerates diastolic dysfunction in hypertensive heart disease through activation of the renin-angiotensin system, with subsequent inflammatory and oxidative stresses and myocardial fibrosis, suggesting that an inhibition of the system is effective for the treatment of diastolic dysfunction in this combined disorder.

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Noninvasive evaluation of cardiac dysfunction by echocardiography in streptozotocin-induced diabetic rats

Cited by 80 publications

References 26 publications

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

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

A Breaker of Advanced Glycation End Products Attenuates Diabetes-Induced Myocardial Structural Changes

Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin–angiotensin system in hypertensive rats

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