Protein Kinase C inhibition ameliorates functional endothelial insulin resistance and Vascular Smooth Muscle Cell hypersensitivity to insulin in diabetic hypertensive rats

Lu, Xiao; Bean, James S.; Kassab, Ghassan S.; Rekhter, Mark D.

doi:10.1186/1475-2840-10-48

Cited by 23 publications

(23 citation statements)

References 36 publications

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“…However, AChstimulated endothelial-dependent vasodilation was not restored [198]. Inconsistent effects of PKC beta inhibition have been demonstrated in patients with T2D.…”

Section: Other Emerging Therapies For T2dmentioning

confidence: 93%

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Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

2013

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■ AbstractType 2 diabetes (T2D) markedly increases the risk of cardiovascular disease. Endothelial dysfunction (ED), an early indicator of diabetic vascular disease, is common in T2D and independently predicts cardiovascular risk. Although the precise pathogenic mechanisms for ED in T2D remain unclear, at inception they probably involve uncoupling of both endothelial nitric oxide synthase activity and mitochondrial oxidative phosphorylation, as well as the activation of vascular nicotinamide adenine dinucleotide phosphate oxidase. The major contributing factors include dyslipoproteinemia, oxidative stress, and inflammation. Therapeutic interventions are designed to target these pathophysiological factors that underlie ED. Therapeutic interventions, including lifestyle changes, antiglycemic agents and lipid-regulating therapies, aim to correct hyperglycemia and atherogenic dyslipidemia and to improve ED. However, high residual cardiovascular risk is seen in both research and clinical practice settings. Well-designed studies of endothelial function in appropriately selected volunteers afford a good opportunity to test new therapeutic interventions, paving the way for clinical trials and utilization in the care of the diabetic patient. However, based on the results from a recent clinical trial, niacin should not be added to a statin in individuals with low high-density lipoprotein cholesterol and very well controlled low-density lipoprotein cholesterol.

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“…However, AChstimulated endothelial-dependent vasodilation was not restored [198]. Inconsistent effects of PKC beta inhibition have been demonstrated in patients with T2D.…”

Section: Other Emerging Therapies For T2dmentioning

confidence: 93%

“…Experimental inhibition of PKC has been shown to ameliorate functional endothelial resistance and smooth muscle cell hypersensitivity in diabetic hypertensive rats [198]. However, AChstimulated endothelial-dependent vasodilation was not restored [198].…”

Section: Other Emerging Therapies For T2dmentioning

confidence: 99%

Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

2013

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“…Not surprisingly, uncorrected obesity is deemed an independent risk factor for the pathogenesis of cardiovascular complications leading to high morbidity and mortality in obese populations. Several mechanisms have been postulated for the etiology of obesity comorbidities including c-Jun N terminal kinase (JNK) activation [15][16][17], protein kinase C induction [18,19], oxidative stress [20,21], altered substrate metabolism [22] and dysregulation of autophagy [23][24][25]. To this end, the present work was designed to examine the possible impact of antioxidant catalase in the regulation of cardiac autophagy and homeostasis in the face of high fat diet-induced obesity.…”

Section: Introductionmentioning

confidence: 99%

Antioxidant catalase rescues against high fat diet-induced cardiac dysfunction via an IKKβ-AMPK-dependent regulation of autophagy

Liang

Shou

Zhao

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Autophagy, a conservative degradation process for long-lived and damaged proteins, participates in a variety of biological processes including obesity. However, the precise mechanism of action behind obesity-induced changes in autophagy still remains elusive. This study was designed to examine the role of the antioxidant catalase in high fat diet-induced changes in cardiac geometry and function as well as the underlying mechanism of action involved with a focus on autophagy. Wild-type (WT) and transgenic mice with cardiac overexpression of catalase were fed low or high fat diet for 20 weeks prior to assessment of myocardial geometry and function. High fat diet intake triggered obesity, hyperinsulinemia, and hypertriglyceridemia, the effects of which were unaffected by catalase transgene. Myocardial geometry and function were compromised with fat diet intake as manifested by cardiac hypertrophy, enlarged left ventricular end systolic and diastolic diameters, fractional shortening, cardiomyocyte contractile capacity and intracellular Ca²⁺ mishandling, the effects of which were ameliorated by catalase. High fat diet intake promoted reactive oxygen species production and suppressed autophagy in the heart, the effects of which were attenuated by catalase. High fat diet intake dampened phosphorylation of inhibitor kappa B kinase β(IKKβ), AMP-activated protein kinase (AMPK) and tuberous sclerosis 2 (TSC2) while promoting phosphorylation of mTOR, the effects of which were ablated by catalase. In vitro study revealed that palmitic acid compromised cardiomyocyte autophagy and contractile function in a manner reminiscent of fat diet intake, the effect of which was significantly alleviated by inhibition of IKKβ, activation of AMPK and induction of autophagy. Taken together, our data revealed that the antioxidant catalase counteracts against high fat diet-induced cardiac geometric and functional anomalies possibly via an IKKβ-AMPK-dependent restoration of myocardial autophagy. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.

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“…contraction; constitutive equation; stress-strain relation; vessel mechanics VASOACTIVITY OF LARGE EPICARDIAL coronary arteries is affected by cardiovascular diseases such as diabetes (14,15), hypertension (14,20), atherosclerosis (11), vasospasm (10,32), and aneurysm (26), which are major risk factors for angina pectoris or myocardial infarction in patients. The constitutive passive and active stress-strain relationships can characterize the vasoactivity and are fundamental for understanding the mechanical behaviors of vascular smooth muscle cell (SMC) in health and disease (5).…”

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confidence: 99%

Biaxial vasoactivity of porcine coronary artery

Huo¹,

Cheng²,

Zhao³

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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The passive mechanical properties of blood vessel mainly stem from the interaction of collagen and elastin fibers, but vessel constriction is attributed to smooth muscle cell (SMC) contraction. Although the passive properties of coronary arteries have been well characterized, the active biaxial stress-strain relationship is not known. Here, we carry out biaxial (inflation and axial extension) mechanical tests in right coronary arteries that provide the active coronary stress-strain relationship in circumferential and axial directions. Based on the measurements, a biaxial active strain energy function is proposed to quantify the constitutive stress-strain relationship in the physiological range of loading. The strain energy is expressed as a Gauss error function in the physiological pressure range. In K ϩ -induced vasoconstriction, the mean Ϯ SE values of outer diameters at transmural pressure of 80 mmHg were 3.41 Ϯ 0.17 and 3.28 Ϯ 0.24 mm at axial stretch ratios of 1.3 and 1.5, respectively, which were significantly smaller than those in Ca 2ϩ -free-induced vasodilated state (i.e., 4.01 Ϯ 0.16 and 3.75 Ϯ 0.20 mm, respectively). The mean Ϯ SE values of the inner and outer diameters in no-load state and the opening angles in zero-stress state were 1.69 Ϯ 0.04 mm and 2.25 Ϯ 0.08 mm and 126 Ϯ 22°, respectively. The active stresses have a maximal value at the passive pressure of 80 -100 mmHg and at the active pressure of 140 -160 mmHg. Moreover, a mechanical analysis shows a significant reduction of mean stress and strain (averaged through the vessel wall). These findings have important implications for understanding SMC mechanics.contraction; constitutive equation; stress-strain relation; vessel mechanics VASOACTIVITY OF LARGE EPICARDIAL coronary arteries is affected by cardiovascular diseases such as diabetes (14, 15), hypertension (14, 20), atherosclerosis (11), vasospasm (10, 32), and aneurysm (26), which are major risk factors for angina pectoris or myocardial infarction in patients. The constitutive passive and active stress-strain relationships can characterize the vasoactivity and are fundamental for understanding the mechanical behaviors of vascular smooth muscle cell (SMC) in health and disease (5). The strain energy function has been widely used to characterize the passive mechanical properties of blood vessels (5,8). For large epicardial coronary arteries, extensive mechanical measurements and analysis were carried out in the passive state (18,19,23,30,33,34).The active mechanical properties of coronary arteries are much known. To date, there are only uniaxial active constitutive length-tension relationships in the circumferential direction of coronary arteries (1, 2, 24, 31). Although some multi-axial active models have been proposed, those have been of theoretical forms not rooted in experimental measurements (25, 36). Clearly, there is a need for multi-axial active mechanical measurements and experimentally determined multi-dimensional active strain energy functions for coronary arteries.The objective ...

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Protein Kinase C inhibition ameliorates functional endothelial insulin resistance and Vascular Smooth Muscle Cell hypersensitivity to insulin in diabetic hypertensive rats

Cited by 23 publications

References 36 publications

Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

Antioxidant catalase rescues against high fat diet-induced cardiac dysfunction via an IKKβ-AMPK-dependent regulation of autophagy

Biaxial vasoactivity of porcine coronary artery

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