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Cardiovascular diseases (CVDs) are a matter of concern worldwide, and mitochondrial dysfunction is one of the major contributing factors. Vascular endothelial dysfunction has a major role in the development of atherosclerosis because of the abnormal chemokine secretion, inflammatory mediators, enhancement of LDL oxidation, cytokine elevation, and smooth muscle cell proliferation. Endothelial cells transfer oxygen from the pulmonary circulatory system to the tissue surrounding the blood vessels, and a majority of oxygen is transferred to the myocardium by endothelial cells, which utilise a small amount of oxygen to generate ATP. Free radicals of oxide are produced by mitochondria, which are responsible for cellular oxygen uptake. Increased mitochondrial ROS generation and reduction in agonist-stimulated eNOS activation and nitric oxide bioavailability were directly linked to the observed change in mitochondrial dynamics, resulting in various CVDs and endothelial dysfunction. Presently, the manuscript mainly focuses on endothelial dysfunction, providing a deep understanding of the various features of mitochondrial mechanisms that are used to modulate endothelial dysfunction. We talk about recent findings and approaches that may make it possible to detect mitochondrial dysfunction as a potential biomarker for risk assessment and diagnosis of endothelial dysfunction. In the end, we cover several targets that may reduce mitochondrial dysfunction through both direct and indirect processes and assess the impact of several different classes of drugs in the context of endothelial dysfunction., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sepsis involves a systemic inflammatory response of multiple endogenous mediators, resulting in many of the injurious and sometimes fatal physiological symptoms of the disease. This systemic activation leads to a compromised vascular response and endothelial dysfunction. Purine nucleotides interact with purinoceptors and initiate a variety of physiological processes that play an important role in maintaining cardiovascular function. The purpose of the present study was to investigate the effects of ATP on vascular function in a lipopolysaccharide (LPS) model of sepsis. LPS induced a significant increase in aortic superoxide production 16 h after injection. Addition of ATP to the organ bath incubation solution reduced superoxide production by the aortas of endotoxemic animals. Reactive Blue, an antagonist of the P2Y receptor, blocked the effect of ATP on superoxide production, and the nonselective P2Y agonist MeSATP inhibited superoxide production. Nitric oxide synthase (NOS) inhibition by L-NAME blocked vascular relaxation and reduced superoxide production in LPS-treated animals. In the presence of L-NAME there was no ATP effect on superoxide production. A vascular reactivity study showed that ATP increased maximal relaxation in LPS-treated animals compared to controls. The presence of ATP induced increases in Akt and endothelial NOS phosphorylated proteins in the aorta of septic animals. ATP reduces superoxide release resulting in an improved vasorelaxant response. Sepsis may uncouple NOS to produce superoxide. We showed that ATP through Akt pathway phosphorylated endothelial NOS and "re-couples" NOS function.

Recent work has demonstrated the production of reactive oxygen and nitrogen species in the vasculature of aging animals. Oxidant induced cell injury triggers the activation of nuclear enzyme poly(ADP ribose) polymerase (PARP) leading to endothelial dysfunction in various pathophysiological conditions (reperfusion, shock, diabetes). Here we studied whether the loss of endothelial function in aging rats is dependent upon the PARP pathway within the vasculature. Young (3 months-old) and aging (22 months-old) Wistar rats were treated for 2 months with vehicle or the PARP inhibitor PJ34. In the vehicle-treated aging animals there was a significant loss of endothelial function, as measured by the relaxant responsiveness of vascular rings to acetylcholine. Treatment with PJ34, a potent PARP inhibitor, restored normal endothelial function. There was no impairment of the contractile function and endothelium-independent vasodilatation in aging rats. Furthermore, we found no deterioration in the myocardial contractile function in aging animals. Thus, intraendothelial PARP activation may contribute to endothelial dysfunction associated with aging.

Patients with diabetes exhibit a high incidence of diabetic cardiomyopathy and vascular complications, which underlie the development of retinopathy, nephropathy, and neuropathy and increase the risk of hypertension, stroke, and myocardial infarction. There is emerging evidence that the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) importantly contributes to the development of endothelial dysfunction in a streptozotocin-induced model of diabetes. We investigated the role of PARP activation in the pathogenesis of cardiac dysfunction in streptozotocin-induced and genetic (nonobese diabetic) models of diabetes in rats and mice. Development of diabetes was accompanied by hyperglycemia, cardiac PARP activation, a selective loss of endothelium-dependent vasodilation in the thoracic aorta, and an early diastolic dysfunction of the heart. Treatment with a novel potent phenanthridinone-based PARP inhibitor, PJ34, starting 1 week after the onset of diabetes, restored normal vascular responsiveness and significantly improved cardiac dysfunction, despite the persistence of severe hyperglycemia. The beneficial effect of PARP inhibition persisted even after several weeks of discontinuation of the treatment. Thus, PARP activation plays a central role in the pathogenesis of diabetic cardiovascular (cardiac as well as endothelial) dysfunction. PARP inhibitors may exert beneficial effects against the development of cardiovascular complications in diabetes.

Oxygen- and nitrogen-derived free radicals and oxidants play an important role in the pathogenesis of diabetic endothelial dysfunction. Recently we proposed the importance of oxidant-induced DNA strand breakage and activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) in the pathogenesis of diabetic endothelial dysfunction. In this study, we tested whether established diabetic endothelial dysfunction is reversible by PARP inhibition. The novel PARP inhibitor PJ34 (10 mg/kg per day PO) was given at various lengths (4 weeks or 3 days) for established streptozotocin-diabetic animals. In addition, we also tested whether incubation of the aortic rings with PJ34 (3 micromol/L) or a variety of other PARP inhibitors for 1 hour affects the diabetic vascular changes. Both 4-week and 3-day PARP-inhibitor treatment of streptozotocin-diabetic mice with established endothelial dysfunction fully reversed the acetylcholine-induced endothelium-dependent relaxations in vitro. Furthermore, 1-hour in vitro incubation of aortae from streptozotocin-diabetic mice with various PARP inhibitors was able to reverse the endothelial dysfunction. ATP, NAD(+), and NADPH levels were markedly reduced in diabetic animals, and PARP-inhibitor treatment was able to restore these alterations. Unexpectedly, pharmacological inhibition of PARP not only prevents the development of the endothelial dysfunction but is also able to rapidly reverse it. Thus, PARP activation and the associated metabolic compromise represent an ongoing process in diabetic blood vessels. Pharmacological inhibition of this process is able to reverse diabetic endothelial dysfunction.

Peroxynitrite and hydroxyl radicals are potent initiators of DNA single-strand breakage, which is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP ribose) polymerase (PARP). In response to high glucose incubation medium in vitro, or diabetes and hyperglycemia in vivo, reactive nitrogen and oxygen species generation occurs. These reactive species trigger DNA single-strand breakage, which induces rapid activation of PARP. PARP in turn depletes the intracellular concentration of its substrate, NAD+, slowing the rate of glycolysis, electron transport, and ATP formation. This process results in acute endothelial dysfunction in diabetic blood vessels. Accordingly, inhibitors of PARP protect against endothelial injury under these conditions. In addition to the direct cytotoxic pathway regulated by DNA injury and PARP activation, PARP also appears to modulate the course of inflammation by regulating the activation of nuclear factor kappaB, and the expression of a number of genes, including the gene for intercellular adhesion molecule 1 and the inducible nitric oxide synthase. The research into the role of PARP in diabetic vascular injury is now supported by novel tools, such as new classes of potent inhibitors of PARP and genetically engineered animals lacking the gene for PARP. Pharmacological inhibition of PARP emerges as a potential approach for the experimental therapy of diabetic vascular dysfunction.

Abstract: Bone marrow-derived mononuclear cells (BMMNCs) secrete anti-inflammatory mediators that protect against acute inflammation. Current evidence suggests that BMMNC transplantation can reduce acute tissue injury caused by systemic inflammation and lung dysfunction. This study evaluated the role of BMMNCs in reducing systemic inflammatory responses to vascular endothelial injury in sepsis. Bone marrow cells were harvested from the tibias and femurs of 12-week-old male Wistar rats; BMMNCs were separated by density centrifugation. Additional rats underwent cecal ligation and puncture (CLP) or similar sham surgery. BMMNCs were injected intravenously 30 min after CLP. The Sham and CLP Control groups were administered PBS. The 7-day survival rate improved markedly in the CLP-BMMNC group compared with that in the Control group. BMMNCs markedly suppressed the serum levels of pro-inflammatory mediators such as tumor necrosis factor-alpha, interleukin-6, and histone H3 at 3, 6, and 12 h after CLP. In the CLP-BMMNC group, the serum levels of syndecan-1, the main component of the vascular endothelial glycocalyx layer, were notably lower than those in the Control group 6 h after CLP. Histological analysis revealed improvement of morphological damages in the CLP-BMMNC group. Ultrastructural analysis revealed that the glycocalyx structure was maintained and the continuity of the vascular endothelial glycocalyx layer was preserved in the BMMNC group, compared with the case for the Control group at 6 and 12 h. Therefore, BMMNC transplantation may provide reduced systemic inflammation and endothelial glycocalyx damage, dramatically improving the survival of rats. These findings provide insights into formulating potential therapeutic strategies against sepsis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

The role of poly (adenosine diphosphate-ribose) synthetase (PARS) in the contractile and relaxant responses of pulmonary arteries injured by ischemia and reperfusion (IR) of splanchnic artery has not been evaluated. We examined these responses by using 3-aminobenzamide, a pharmacological inhibitor of PARS. IR models in rats were induced by clamping the superior mesenteric artery for 60 min, followed by release of the clamp for 60 min. In the 2 treated groups, 5 or 10 mg/kg of 3-aminobenzamide was administered as an IV bolus at 10 min before reperfusion, followed by infusion rates of 5 and 10 mg.kg(-1).h(-1), respectively, during the period of reperfusion (IR + PARS inhibitor 5 and 10 groups). In the vehicle-treated group, 3-aminobenzamide was not given, but IV saline was administered (IR group). In the control group, surgery was performed, but the superior mesenteric artery was not occluded (sham group). The pulmonary arteries were isolated, and effects of drugs were evaluated in vitro. The IR group showed no attenuation of the contractile responses of the pulmonary artery to phenylephrine. The relaxant responses to endothelium-dependent vasodilators, acetylcholine, and A23187 in the IR group were significantly inhibited when compared with the sham group. The reduction in the relaxant response to endothelium-dependent vasodilators was improved in the IR + PARS inhibitor 5 and 10 groups when compared with the IR group. We concluded that IR attenuated the relaxant responses of the pulmonary artery to endothelium-dependent vasodilators and that PARS inhibitors ameliorate the reduction in the relaxant response.