Impaired Endothelium-Dependent Hyperpolarization Underlies Endothelial Dysfunction during Early Metabolic Challenge: Increased ROS Generation and Possible Interference with NO Function

Abstract

Endothelial dysfunction is a hallmark of diabetic vasculopathies. Although hyperglycemia is believed to be the culprit causing endothelial damage, the mechanism underlying early endothelial insult in prediabetes remains obscure. We used a nonobese high-calorie (HC)-fed rat model with hyperinsulinemia, hypercholesterolemia, and delayed development of hyperglycemia to unravel this mechanism. Compared with aortic rings from control rats, HC-fed rat rings displayed attenuated acetylcholinemediated relaxation. While sensitive to nitric oxide synthase (NOS) inhibition, aortic relaxation in HC-rat tissues was not affected by blocking the inward-rectifier potassium (Kir) channels using BaCl 2 . Although Kir channel expression was reduced in HC-rat aorta, Kir expression, endothelium-dependent relaxation, and the BaCl 2 -sensitive component improved in HC rats treated with atorvastatin to reduce serum cholesterol. Remarkably, HC tissues demonstrated increased reactive species (ROS) in smooth muscle cells, which was reversed in rats receiving atorvastatin. In vitro ROS reduction, with superoxide dismutase, improved endothelium-dependent relaxation in HC-rat tissues. Significantly, connexin-43 expression increased in HC aortic tissues, possibly allowing ROS movement into the endothelium and reduction of eNOS activity. In this context, gap junction blockade with 18-b-glycyrrhetinic acid reduced vascular tone in HC rat tissues but not in controls. This reduction was sensitive to NOS inhibition and SOD treatment, possibly as an outcome of reduced ROS influence, and emerged in BaCl 2 -treated control tissues. In conclusion, our results suggest that early metabolic challenge leads to reduced Kir-mediated endotheliumdependent hyperpolarization, increased vascular ROS potentially impairing NO synthesis and highlight these channels as a possible target for early intervention with vascular dysfunction in metabolic disease. SIGNIFICANCE STATEMENTThe present study examines early endothelial dysfunction in metabolic disease. Our results suggest that reduced inwardrectifier potassium channel function underlies a defective endothelium-mediated relaxation possibly through alteration of nitric oxide synthase activity. This study provides a possible mechanism for the augmentation of relatively small changes in one endothelium-mediated relaxation pathway to affect overall endothelial response and highlights the potential role of inwardrectifier potassium channel function as a therapeutic target to treat vascular dysfunction early in the course of metabolic disease.

Worsening baroreflex sensitivity on progression to type 2 diabetes: localized vs. systemic inflammation and role of antidiabetic therapy

“…Out of the STZ-injected rats developing T2D, those receiving insulin injections (INS) rats consumed more calories than the average consumption of T2D rats for 2-wk duration of insulin treatment (data not shown). Similar to our previous studies (2,3,20), MHC feeding did not result in a weight difference compared with control rats; however, rats developing T2D after STZ injection appeared to lose weight starting at week 9 (Fig. 1B).…”

“…As such, we hypothesize that the major mediator of development of CAN in T2D with progressive metabolic deterioration, from insulin resistance to hyperglycemia, is the extent and localization of inflammation. For this purpose, we used our previously developed rat model of early metabolic challenge (2,3,20) and extended the investigation by induction of T2D using sequential injections of lowdose streptozotocin (STZ). We also investigated the effect of metformin, pioglitazone, insulin, or their combinations on the inflammatory and autonomic changes at this late stage.…”

Untargeted Metabolomics of Fermented Rice Using UHPLC Q-TOF MS/MS Reveals an Abundance of Potential Antihypertensive Compounds

“…In recent years, cereal grains such as rice have attracted much scientific attention [1] because they contain phenolic compounds such as quercetin, ferulic acid, and salicylic acid [2] which have strong antioxidant abilities [3]. Over the years, oxidative stress has been shown to play a key role in the pathogenesis of hypertension [4,5] since reactive oxygen species can cause endothelial dysfunction [6] leading to arterial stiffness in humans [7,8]. One popular physiological mechanism of hypertension is the renin-aldosterone-angiotensin system (RAAS) [9].…”

Modulatory Effect of Intermittent Fasting on Adipose Tissue Inflammation: Amelioration of Cardiovascular Dysfunction in Early Metabolic Impairment

“…In fact, obese patients with insulin resistance had systemic arterial dysfunction concurrent with high M1 ATMs and TNFα mRNA in SAT and elevated serum C reactive protein (CRP), indicating a proinflammatory state (Apovian et al, 2008). Interestingly, recent studies on a prediabetic rat model showed that mildly increased caloric intake led to clear cardiovascular manifestations even in absence of overt hyperglycemia, increased body weight, or high blood pressure (Al-Assi et al, 2018;Alaaeddine et al, 2019;Elkhatib et al, 2019). Significantly, the observed endothelial dysfunction and CAN were linked to localized PVAT inflammation with neither inflammatory changes in other adipose pool nor systemic involvement (Al-Assi et al, 2018;Alaaeddine et al, 2019;Elkhatib et al, 2019).…”

“…Interestingly, recent studies on a prediabetic rat model showed that mildly increased caloric intake led to clear cardiovascular manifestations even in absence of overt hyperglycemia, increased body weight, or high blood pressure (Al-Assi et al, 2018;Alaaeddine et al, 2019;Elkhatib et al, 2019). Significantly, the observed endothelial dysfunction and CAN were linked to localized PVAT inflammation with neither inflammatory changes in other adipose pool nor systemic involvement (Al-Assi et al, 2018;Alaaeddine et al, 2019;Elkhatib et al, 2019). This early PVAT involvement in the course of metabolic disease is of particular relevance given the close anatomical proximity between PVAT and the cardiovascular tissue.…”