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Gene Therapy for Cardiovascular Diseases
Published in Yashwant Pathak, Gene Delivery, 2022
Dhwani Thakkar, Vandit Shah, Jigna Shah
Progressive increase in pulmonary artery pressure is known as pulmonary hypertension. Etiology of primary pulmonary hypertension (PPH) is unknown; however, mutation in Bone Morphogenic Protein Receptor II (BMPR-II) is reported in scattered cases of PPH.38 Secondary pulmonary hypertension is caused due to chronic thrombotic or embolic diseases, chronic hypoxia, collagen vascular disease, congenital heart diseases, chronic obstructive pulmonary diseases, and exposure to certain drugs. Also, right ventricle hypertrophy, plexogenic pulmonary arteriopathy, and vascular remodeling in small- and medium-sized pulmonary vessels is observed in many cases. Prostacyclin, inhaled nitric oxide, endothelin receptor antagonists, and calcium channel blockers have all been used to treat pulmonary hypertension, but they have all failed to treat PPH, since it is progressive and malignant. Various genes, such as e-NOS, prostacyclin synthase, MCP-1, prepro-calcitonin gene related peptide, VEGF, and atrial natriuretic peptide, are utilized to reduce pulmonary artery vasospasm and cellular proliferation, although these strategies are only successful in animal models.35,39,40
Eicosanoids and Hypertension in Pregnancy
Published in Murray D. Mitchell, Eicosanoids in Reproduction, 2020
Scott W. Walsh, Valerie M. Parisi
A considerable amount of data indicates that prostacyclin production is decreased in preeclampsia. The first evidence came in 1980 from studies on vascular tissues by Remuzzi et al.,40 Bussolino et al.,41 and Downing at al.42 Remuzzi and colleagues40 reported that prostacyclin production was decreased in umbilical arteries and placental veins obtained from five patients with severe preeclampsia. Bussolino et al.41 examined vascular prostacyclin production in vessels obtained from normal and preeclamptic pregnancies. They found that prostacyclin production was decreased in placental veins, subcutaneous vessels and uterine vessels in severely preeclamptic patients. Downing et al.42 examined the enzymatic kinetics of prostacyclin synthase in umbilical arteries. They found that the enzyme activity was the same in normal and hypertensive umbilical cords but the hypertensive cords contained less enzyme. Additional studies confirmed the decreased vascular production of prostacyclin in hypertensive pregnancies.43–45 Prostacyclin production is, therefore, decreased in umbilical arteries, placental veins, uterine vessels and subcutaneous vessels obtained from preeclamptic women, as compared to normally pregnant women.
Micronutrients in Prevention and Improvement of the Standard Therapy in Diabetes
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
In a clinical study involving 9 patients with type 1 diabetes, the effect of benfotiamine, a lipophilic derivative of thiamine, together with slow-release alpha-lipoic acid on glycemic status was evaluated by measuring hyperglycemia, intracellular AGE formation, hexosamine pathway activity, and prostacyclin. The results showed that the levels of AGE and monocyte hexosamine–modified proteins were increased, whereas the activity of prostacyclin synthase was decreased in diabetic patients. Treatment with benfotiamine together with slow-release alpha-lipoic acid did not affect hyperglycemia, but it normalized the AGE level and the activity of prostacyclin synthase and reduced monocyte hexosamine–modified proteins.186 Zycose is a new drug released in 2006 for the treatment of diabetes. It contains benfotiamine (150 mg), benzamine (850 mg), a proprietary blend of para-aminobenzoic acid (PABA), vitamin E, and alpha-lipoic acid. Zycose has been shown to improve vascular dysfunction, neuropathy, nephropathy, and nerve function.187
Effect of quercetin on the pharmacokinetics of selexipag and its active metabolite in beagles
Published in Pharmaceutical Biology, 2022
Shun-bin Luo, Er-min Gu, Yu-ao Chen, Shi-chen Zhou, Chen Fan, Ren-ai Xu
Characterised by a gradual increase in pulmonary vascular resistance and pulmonary artery pressure, Pulmonary Arterial Hypertension (PAH) is a progressive, debilitating and chronic life-threatening disease (Sardana et al. 2016; Bruderer et al. 2017; Bhadru et al. 2019; Highland et al. 2019; Ilyin et al. 2019; Klose et al. 2019, 2021; Yazıcı & Güngör 2019; A Xe Lsen et al. 2021; Genecand et al. 2021). PAH may cause right ventricular dysfunction and potential failure and the average survival time of patients is only 2.8 years if not treated (Gnerre et al. 2018; Highland et al. 2019). There is strong evidence to support early intervention and the achievement of all treatment objectives with monotherapy or combination therapy has been critical to date (Ilyin et al. 2019). Prostacyclin, produced by prostaglandin H2 (PGH2) endothelial cells via prostacyclin synthase, is a potent vasodilator with anti-proliferative, anti-thrombotic, and anti-inflammatory effects (Bhadru et al. 2019). The role of prostacyclin or prostacyclin receptor (IP receptor) agonists in the treatment of PAH is reasonable because PAH is associated with vasoconstriction, proliferation, and thrombosis (Gnerre et al. 2018).
Epoprostenol for the treatment of pulmonary arterial hypertension
Published in Expert Review of Clinical Pharmacology, 2021
María José Cristo Ropero, Alejandro Cruz-Utrilla, María Pilar Escribano-Subias
Prostanoids can be divided into prostaglandins (PGD2, PGE2, PGI2 or prostacyclin, and PGF2) and thromboxane. They act on G-protein-coupled prostanoid IP receptors. Within the pulmonary vasculature, these receptors could be categorized as relaxant (IP, DP1, EP2, EP4) and contractile receptors (EP1, EP3, FP, and TP). Prostacyclin synthase produces prostacyclin within vascular endothelial cells. Epoprostenol acts as a synthetic analog of prostaglandin I2 in endothelial cells with a vasodilatory effect. The receptor’s activation in other cells produces anti-inflammatory, antiaggregating, and antiproliferative effects (Figure 1). Also, smooth muscle cell proliferation is slowed via transformation of ATP to AMP and an increase in protein kinase A activity. Two main metabolites of have been identified as follows: 6-keto-prostacyclin F1α, the more suitable marker of plasma concentrations of the drug and formed by hydration; and 6,15-diketo-13,14-dihydro-prostacyclin F1α, produced by enzymatic degradation. This drug has a short elimination half-life (3–6 minutes) in the human blood stream [42].
Tumor necrosis factor alpha expression is increased in maternal microvascular endothelial cells in preeclampsia
Published in Hypertension in Pregnancy, 2021
Previously, we observed PE MVEC expression of apelin was lower than in normal MVEC (13). Apelin has been shown to have cardioprotective effects with an apparent antagonistic relationship between the apelinergic system and the renin-angiotensin system; specifically angiotensin-II (36–39), with apelin exhibiting angiogenic and vasodilatory effects. In humans, apelin produces dose-dependent relaxation of preconstricted ex vivo mesenteric arteries mediated by nitric oxide (40). In the vasculature, the endothelium appears to be the predominant source of apelin synthesis, with only low levels of apelin being observed in vascular smooth muscle (36). Here, we report that TNFα treatment further decreases apelin mRNA expression in PE MVEC, but not in cells isolated from normal pregnancies, suggesting a vulnerability in PE MVEC to the protective qualities of apelin, namely in antagonizing vasopressor and antiangiogenic phenotypes characteristic of PE. In addition, while the decrease in prostacyclin synthase expression in PE MVEC by TNFα treatment was not statistically significant, inhibition of NFκB did elevate prostacyclin synthase expression levels in TNFα treated PE MVEC, suggesting that TNFα plays an important role in regulating prostacyclin levels and thus contribute to elevated blood pressure by impaired prostacyclin production.