Methylglyoxal (MGO), a glycolysis by-product and precursor to advanced glycation endproducts (AGEs), is associated with glucose intolerance, type 2 diabetes, and vascular dysfunction. This study examined the long-term effects of elevated MGO on blood pressure, insulin sensitivity, and vascular function in healthy mice. Male C57Bl/6J mice were assigned to control (n = 16) or MGO-treated groups (50 mM in drinking water for 13 weeks, n = 16). Measurements included body weight, fasting plasma glucose, water consumption, blood pressure, and analysis of plasma/tissue for MGO, AGEs, glyoxalase activity, and inflammation markers. Endothelial function was assessed using wire myography, and the response of human placental arteries to MGO-modified insulin was evaluated. MGO treatment significantly increased plasma MGO (123.3%, p < 0.001), AGEs MG-H1 (208.6%, p < 0.001) and CEL (64.3%, p < 0.001), and AGEs in the heart, kidney, and liver, along with body weight (+ 6.4%, p = 0.032) and blood pressure (systolic + 5.0%, p = 0.046; diastolic + 6.5%, p = 0.043). Glucose sensitivity and endothelial function remained unaffected. CRP levels rose, and MGO-modified insulin enhanced vascular contraction. In conclusion, chronic MGO exposure increased plasma MGO to diabetic-like levels, raised body weight and blood pressure, and did not alter glucose sensitivity or endothelial function. Modification of insulin by MGO may contribute to MGO-related changes in blood pressure.
Preeclampsia is a multifaceted syndrome that includes maternal vascular dysfunction. We hypothesize that increased placental glycolysis and hypoxia in preeclampsia lead to increased levels of methylglyoxal (MGO), consequently causing vascular dysfunction.
Limited literature sources implicate mast-cell mediator chymase in the pathologies of pulmonary hypertension and pulmonary fibrosis. However, there is no evidence on the contribution of chymase to the development of pulmonary hypertension associated with lung fibrosis, which is an important medical condition linked with increased mortality of patients who already suffer from a life-threatening interstitial lung disease. The aim of this study was to investigate the role of chymase in this particular pulmonary hypertension form, by using a bleomycin-induced pulmonary hypertension model. Chymase inhibition resulted in attenuation of pulmonary hypertension and pulmonary fibrosis, as evident from improved haemodynamics, decreased right ventricular remodelling/hypertrophy, pulmonary vascular remodelling and lung fibrosis. These beneficial effects were associated with a strong tendency of reduction in mast cell number and activity, and significantly diminished chymase expression levels. Mechanistically, chymase inhibition led to attenuation of transforming growth factor β1 and matrix-metalloproteinase-2 contents in the lungs. Furthermore, chymase inhibition prevented big endothelin-1-induced vasoconstriction of the pulmonary arteries. Therefore, chymase plays a role in the pathogenesis of pulmonary hypertension associated with pulmonary fibrosis and may represent a promising therapeutic target. In addition, this study may provide valuable insights on the contribution of chymase in the pulmonary hypertension context, in general, regardless of the pulmonary hypertension form.
Objectives To compare DNA synthesis in isolated arteries of normotensive and hypertensive rats and to evaluate whether removal of the endothelium affects this process. Design Carotid and renal artery segments were isolated from normotensive Wistar, Wistar-Kyoto (WKY) and Sprague-Dawley rats, and from spontaneously hypertensive rats (SHR), transgenic Sprague-Dawley rats harbouring the mouse Ren-2 gene and from WKY rats rendered hypertensive by aortic coarctation. Methods Artery segments were exposed in vitro to serum with or without previous gentle removal of the endothelium. Nuclear incorporation of the thymidine analogue 5-bromo-2‘-deoxyuridine was visualized by immunocytochemistry and the percentage of labelled medial nuclei was determined. Results In both types of artery, obtained from 6-week-old WKY rats and from 6-week-old SHR, removal of endothelium increased the percentage of 5-bromo-2‘-deoxyuridine-labelled medial nuclei (L%). Also, in the arteries of 20-week-old Wistar rats, WKY rats and WKY rats rendered hypertensive by aortic coarctation and in vessels of 11-week-old Sprague-Dawley rats and Sprague-Dawley rats harbouring the mouse Ren-2 gene, removal of endothelium increased L%. Conversely, in the arteries of 20-week-old SHR removal of the endothelium did not alter L%. Furthermore, maximally stimulated DNA synthesis was considerably smaller in de-endothelialized arteries of adult SHR than in denuded vessels from the other strains and models. Conclusion These findings confirm that the endothelium can reduce DNA synthesis in the intact rat arterial smooth muscle. This effect is not modified by hypertension, but is selectively reduced in the arteries of adult SHR.
We evaluated responses of peripheral resistance arterial smooth muscle to α 1 ‐adrenoceptor stimulation in a rat model of heart failure in relation to neurohumoral changes, wall structure, receptor density and cellular calcium handling. Plasma samples and third order mesenteric artery side‐branches were obtained from Wistar rats after induction of left ventricular infarction (MI) or sham surgery. Vessels were denuded of endothelium, sympathectomized, depleted of neuropeptides, and mounted in a myograph for recording of isometric force development in response to calcium, agonist and high potassium. Also, the morphology of these preparations was determined. Separate vessel segments were used in radioligand binding assays with [ 3 H]‐prazosin. At 1 week after MI, circulating plasma levels of adrenaline, angiotensin II, atrial natriuretic factor (ANF) and vasopressin were significantly elevated. At 5 weeks only a significant elevation of ANF persisted. At 5 weeks after MI, the structure of the vessels and responsiveness to high potassium or Bay K 8466 (10 −6 mol l −1 ) were not modified. Yet, at this stage, sensitivity to phenylephrine was increased (pD 2 : 6.24±0.04 vs 5.98±0.04 for controls) while maximal contractile responses to phenylephrine in the presence of 2.5 mmol l −1 calcium (2.26±0.28 vs 3.53±0.34 N m −1 ) and the sensitivity to calcium in the presence of phenylephrine (pD 2 : 2.81±0.22 vs 3.74±0.16) were reduced. Responses to the agonist in calcium‐free solution and the calcium sensitivity in the presence of 125 mmol l −1 potassium or of phorbol myristate acetate (PMA, 10 −6 mol l −1 ) were not altered. At 5 weeks after MI, the density of prazosin binding sites was not reduced (4.04±1.40 vs 2.29±0.21 fmol μg −1 DNA in controls). In conclusion, myocardial infarction leads in the rat to a reduction of contractile responses of mesenteric resistance arterial smooth muscle to α 1 ‐adrenoceptor stimulation. This seems to involve impaired agonist‐stimulated calcium influx. British Journal of Pharmacology (1997) 120 , 1505–1512; doi: 10.1038/sj.bjp.0701089
