Dysregulation of nitric oxide synthases during early and late pathophysiological conditions of diabetes mellitus leads to amassing of microvascular impedement

Suresh, Varuna; Reddy, Amala

doi:10.1007/s40200-021-00799-y

Cited by 15 publications

(10 citation statements)

References 99 publications

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“…Increased oxidative stress is implicated in the pathogenesis of the various vascular complications of diabetes, including in diabetic angiopathy of the lower extremities [ 66 , 67 , 68 ]. It is well-known that abnormal endothelial-dependent vasodilation in diabetic patients is at least partially attributed to the reactive oxygen species that are primarily generated by up-regulated NOXs and downregulated endothelial nitric oxide synthase [ 69 , 70 ]. The increase in ROS levels and the decrease in nitric oxide are known to cause irreversible damage to the vascular endothelial cells through apoptosis [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

Single Nucleotide Polymorphisms of the RAC1 Gene as Novel Susceptibility Markers for Neuropathy and Microvascular Complications in Type 2 Diabetes

2023

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Single nucleotide polymorphisms (SNP) in the RAC1 (Rac family small GTPase 1) gene have recently been linked to type 2 diabetes (T2D) and hyperglycemia due to their contribution to impaired redox homeostasis. The present study was designed to determine whether the common SNPs of the RAC1 gene are associated with diabetic complications such as neuropathy (DN), retinopathy (DR), nephropathy, angiopathy of the lower extremities (DA), and diabetic foot syndrome. A total of 1470 DNA samples from T2D patients were genotyped for six common SNPs by the MassArray Analyzer-4 system. The genotype rs7784465-T/C of RAC1 was associated with an increased risk of DR (p = 0.016) and DA (p = 0.03) in males, as well as with DR in females (p = 0.01). Furthermore, the SNP rs836478 showed an association with DR (p = 0.005) and DN (p = 0.025) in males, whereas the SNP rs10238136 was associated with DA in females (p = 0.002). In total, three RAC1 haplotypes showed significant associations (FDR < 0.05) with T2D complications in a sex-specific manner. The study’s findings demonstrate, for the first time, that the RAC1 gene’s polymorphisms represent novel and sex-specific markers of neuropathy and microvascular complications in type 2 diabetes, and that the gene could be a new target for the pharmacological inhibition of oxidative stress as a means of preventing diabetic complications.

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Section: Discussionmentioning

confidence: 99%

Single Nucleotide Polymorphisms of the RAC1 Gene as Novel Susceptibility Markers for Neuropathy and Microvascular Complications in Type 2 Diabetes

2023

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“…Atherosclerosis-induced hypercholesterolemia is a cardiovascular progression coupled with type 2 diabetes mellitus [ 106 ], which increases reactive oxygen species (ROS), and subsequent eNOS degradation, releasing endothelin 1-induced vasoconstriction [ 107 ]. Changes in cholesterol levels due to glucose intolerance induce dysregulation of ICAM-1 and VCAM-1 [ 108 ].…”

Section: Discussionmentioning

confidence: 99%

Partial Synthetic PPARƳ Derivative Ameliorates Aorta Injury in Experimental Diabetic Rats Mediated by Activation of miR-126-5p Pi3k/AKT/PDK 1/mTOR Expression

et al. 2022

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Type 2 diabetes mellitus (T2D) is a world wild health care issue marked by insulin resistance, a risk factor for the metabolic disorder that exaggerates endothelial dysfunction, increasing the risk of cardiovascular complications. Peroxisome proliferator-activated receptor PPAR) agonists have therapeutically mitigated hyperlipidemia and hyperglycemia in T2D patients. Therefore, we aimed to experimentally investigate the efficacy of newly designed synthetic PPARα/Ƴ partial agonists on a High-Fat Diet (HFD)/streptozotocin (STZ)-induced T2D. Female Wistar rats (200 ± 25 g body weight) were divided into four groups. The experimental groups were fed the HFD for three consecutive weeks before STZ injection (45 mg/kg/i.p) to induce T2D. Standard reference PPARƳ agonist pioglitazone and the partial synthetic PPARƳ (PIO; 20 mg/kg/BW, orally) were administered orally for 2 weeks after 72 h of STZ injection. The aorta tissue was isolated for biological ELISA, qRT-PCR, and Western blotting investigations for vascular inflammatory endothelial mediators endothelin-1 (ET-1), intracellular adhesion molecule 1 (ICAM-1), E-selectin, and anti-inflammatory vasoactive intestinal polypeptide (VIP), as well as microRNA126-5p and p-AKT/p-Pi3k/p-PDK-1/p-mTOR, endothelial Nitric Oxide Synthase (eNOS) immunohistochemical staining all are coupled with and histopathological examination. Our results revealed that HFD/STZ-induced T2D increased fasting blood glucose, ET-1, ICAM-1, E-selectin, and VIP levels, while decreasing the expression of both microRNA126-5p and p-AKT/p-Pi3k/p-PDK-1/p-mTOR phosphorylation. In contrast, the partial synthetic PPARƳ derivative evidenced a vascular alteration significantly more than reference PIO via decreasing (ET-1), ICAM-1, E-selectin, and VIP, along with increased expression of microRNA126-5p and p-AKT/p-Pi3k/p-PDK-1/p-mTOR. In conclusion, the partial synthetic PPARƳ derivative significantly affected HFD/STZ-induced T2D with vascular complications in the rat aorta.

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“…In hypertension, the mechanisms involved in changes in NO metabolism are decreased NO production and increased NO inactivation [ 93 , 94 ]. A reduced NO synthesis can result from: a deficiency in the substrate of NO synthase, L-arginine [ 95 ]; a high concentration of endogenous NO synthase inhibitors [ 96 ]; deficiency of cofactor for NO endothelial synthesis [ 97 ]; reduced expression of e-NOS [ 98 ]; an alteration of the transduction signals leading to the uncoupling of endothelial NO synthase [ 99 ]; …”

Section: Introductionmentioning

confidence: 99%

The Contribution of Gut Microbiota and Endothelial Dysfunction in the Development of Arterial Hypertension in Animal Models and in Humans

Maiuolo

Carresi

Gliozzi

et al. 2022

IJMS

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The maintenance of the physiological values of blood pressure is closely related to unchangeable factors (genetic predisposition or pathological alterations) but also to modifiable factors (dietary fat and salt, sedentary lifestyle, overweight, inappropriate combinations of drugs, alcohol abuse, smoking and use of psychogenic substances). Hypertension is usually characterized by the presence of a chronic increase in systemic blood pressure above the threshold value and is an important risk factor for cardiovascular disease, including myocardial infarction, stroke, micro- and macro-vascular diseases. Hypertension is closely related to functional changes in the endothelium, such as an altered production of vasoconstrictive and vasodilator substances, which lead to an increase in vascular resistance. These alterations make the endothelial tissue unresponsive to autocrine and paracrine stimuli, initially determining an adaptive response, which over time lead to an increase in risk or disease. The gut microbiota is composed of a highly diverse bacterial population of approximately 1014 bacteria. A balanced intestinal microbiota preserves the digestive and absorbent functions of the intestine, protecting from pathogens and toxic metabolites in the circulation and reducing the onset of various diseases. The gut microbiota has been shown to produce unique metabolites potentially important in the generation of hypertension and endothelial dysfunction. This review highlights the close connection between hypertension, endothelial dysfunction and gut microbiota.

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Dysregulation of nitric oxide synthases during early and late pathophysiological conditions of diabetes mellitus leads to amassing of microvascular impedement

Cited by 15 publications

References 99 publications

Single Nucleotide Polymorphisms of the RAC1 Gene as Novel Susceptibility Markers for Neuropathy and Microvascular Complications in Type 2 Diabetes

Single Nucleotide Polymorphisms of the RAC1 Gene as Novel Susceptibility Markers for Neuropathy and Microvascular Complications in Type 2 Diabetes

Partial Synthetic PPARƳ Derivative Ameliorates Aorta Injury in Experimental Diabetic Rats Mediated by Activation of miR-126-5p Pi3k/AKT/PDK 1/mTOR Expression

The Contribution of Gut Microbiota and Endothelial Dysfunction in the Development of Arterial Hypertension in Animal Models and in Humans

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