Impaired cross-talk between NO and hyperpolarization in myoendothelial feedback: a novel therapeutic target in early endothelial dysfunction of metabolic disease

Alaaeddine, Rana; Mroueh, Ali; Gust, Stephen L.; Eid, Ali H.; Plane, Frances; El-Yazbi, Ahmed F.

doi:10.1016/j.coph.2019.03.007

Cited by 10 publications

(12 citation statements)

References 87 publications

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“…This was despite the observation that Cx43 subunit expression levels increased in aortic tissues from HC-fed rats. Cx43 upregulation is in line with previous literature showing that, while the vascular expression of some connexin subunits (Cx37 and 40) tended to decrease in metabolic disease, Cx43 expression was found to increase (Alaaeddine et al, 2019). Cx43 is highly expressed in VSMCs and endothelial cells, specifically at the myoendothelial junction (Abed et al, 2014) and is thought to increase in metabolic disturbance as a consequence of increased ERK phosphorylation (Ho et al, 2013), a common observation in the vascular tissue in our rat model (Al-Assi et al, 2018;Elkhatib et al, 2019).…”

Section: Discussionsupporting

confidence: 91%

“…Deterioration of endothelial function starts at early stages of insulin resistance in the form of decreased NO bioavailability, impaired prostacyclin production, or increased endothelial vasoconstrictor production (Du et al, 2006;Picchi et al, 2006;Duncan et al, 2007;Polovina and Potpara, 2014). On the other hand, emerging evidence describes a role for endotheliumdependent hyperpolarization (EDH) in regulating the overall endothelial response, including NO-mediated relaxation (Fancher et al, 2018;Alaaeddine et al, 2019). While few studies recorded observational changes in EDH-type relaxation in animal models of insulin resistance and metabolic disease (Miller et al, 1998;Gradel et al, 2018), our knowledge still lacks a detailed mechanistic explanation behind the contribution of EDH to the integrative endothelial response in this stage.…”

Section: Introductionmentioning

confidence: 99%

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

Alaaeddine

Elkhatib

Mroueh

et al. 2019

J Pharmacol Exp Ther

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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

Alaaeddine

Elkhatib

Mroueh

et al. 2019

J Pharmacol Exp Ther

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“…Potassium channels are known to play an important role in vasodilation [24,25,26]. Thus, we wished to determine the of role of these channels in OME-induced relaxation.…”

Section: Resultsmentioning

confidence: 99%

Marjoram Relaxes Rat Thoracic Aorta Via a PI3-K/eNOS/cGMP Pathway

et al. 2019

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Despite pharmacotherapeutic advances, cardiovascular disease (CVD) remains the primary cause of global mortality. Alternative approaches, such as herbal medicine, continue to be sought to reduce this burden. Origanum majorana is recognized for many medicinal values, yet its vasculoprotective effects remain poorly investigated. Here, we subjected rat thoracic aortae to increasing doses of an ethanolic extract of Origanum majorana (OME). OME induced relaxation in a dose-dependent manner in endothelium-intact rings. This relaxation was significantly blunted in denuded rings. N(ω)-nitro-l-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) significantly reduced the OME-induced vasorelaxation. Cyclic guanosine monophosphate (cGMP) levels were also increased by OME. Moreover, wortmannin or LY294002 significantly reduced OME-induced vasorelaxation. Blockers of ATP-sensitive or Ca2+-activated potassium channels such as glibenclamide or tetraethylamonium (TEA), respectively, did not significantly affect OME-induced relaxation. Similarly, verapamil, a Ca2+ channel blocker, indomethacin, a non-selective cyclooxygenase inhibitor, and pyrilamine, a H1 histamine receptor blocker, did not significantly modulate the observed relaxation. Taken together, our results show that OME induces vasorelaxation via an endothelium-dependent mechanism involving the phosphoinositide 3-kinase (PI3-K)/ endothelial nitric oxide (NO) synthase (eNOS)/cGMP pathway. Our findings further support the medicinal value of marjoram and provide a basis for its beneficial intake. Although consuming marjoram may have an antihypertensive effect, further studies are needed to better determine its effects in different vascular beds.

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“…Furthermore, overexpression of ACE2 prevents cardiac hypertrophy in hypertensive rats (Sriramula et al, 2011). In a related study, ACE2 mRNA expression was markedly reduced in rat models of hypertension and was associated with defects in cardiac contractility, increased AngII levels, and upregulation of hypoxia induced genes (Alaaeddine et al, 2019). Drugs used to treat hypertension, such as the AT 1 R blockers (ARBs), upregulate myocardial expression of ACE2 and reduce levels of inflammatory markers like MCP-1, interleukins and NF-B (Sukumaran et al, 2012).…”

Section: Ace2 and Cardiovascular Diseasesmentioning

confidence: 92%

Dysregulation of Angiotensin Converting Enzyme 2 Expression and Function in Comorbid Disease Conditions Possibly Contributes to Coronavirus Infectious Disease 2019 Complication Severity

et al. 2020

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ACE2 has emerged as a double agent in the COVID-19 ordeal being physiologically protective yet virally conducive. The identification of ACE2 in as many as 72 tissues suggests that extrapulmonary invasion and damage is likely, which indeed has already been demonstrated by cardiovascular and gastro-intestinal symptoms. On the other hand, identifying ACE2 dysregulation in patients with co-morbidities may offer insight as to why COVID-19 symptoms are often more severe in these individuals. This may be attributed to a pre-existing proinflammatory state that is further propelled with the cytokine storm induced by SARS-CoV-2 infection or the loss of functional ACE2 expression as a result of viral internalization. Here, we aim to characterize the distribution and role of ACE2 in various organs in order to highlight the scope of damage that may arise upon SARS-CoV-2 invasion. Furthermore, by examining the disruption of ACE2 in several co-morbid diseases, we offer insight into potential causes of increased severity of COVID-19 symptoms in certain individuals.

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Impaired cross-talk between NO and hyperpolarization in myoendothelial feedback: a novel therapeutic target in early endothelial dysfunction of metabolic disease

Cited by 10 publications

References 87 publications

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

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

Marjoram Relaxes Rat Thoracic Aorta Via a PI3-K/eNOS/cGMP Pathway

Dysregulation of Angiotensin Converting Enzyme 2 Expression and Function in Comorbid Disease Conditions Possibly Contributes to Coronavirus Infectious Disease 2019 Complication Severity

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