| 91. |
- Szekeres, Ferenc L. M., et al.
(författare)
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A small molecule inhibitor of Nox2 and Nox4 improves contractile function after ischemia–reperfusion in the mouse heart
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The NADPH oxidase enzymes Nox2 and 4, are important generators of Reactive oxygen species (ROS). These enzymes are abundantly expressed in cardiomyocytes and have been implicated in ischemia–reperfusion injury. Previous attempts with full inhibition of their activity using genetically modified animals have shown variable results, suggesting that a selective and graded inhibition could be a more relevant approach. We have, using chemical library screening, identified a new compound (GLX481304) which inhibits Nox 2 and 4 (with IC50 values of 1.25 µM) without general antioxidant effects or inhibitory effects on Nox 1. The compound inhibits ROS production in isolated mouse cardiomyocytes and improves cardiomyocyte contractility and contraction of whole retrogradely (Langendorff) perfused hearts after a global ischemia period. We conclude that a pharmacological and partial inhibition of ROS production by inhibition of Nox 2 and 4 is beneficial for recovery after ischemia reperfusion and might be a promising venue for treatment of ischemic injury to the heart.
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| 92. |
- van Wieringen, Tijs, 1979-
(författare)
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Intra- and Extracellular Modulation of Integrin-directed Connective Tissue Cell Contraction
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- All blood vessels in the microvasculature are embedded in loose connective tissue, which regulates the transport of fluid to and from tissues. The intersti-tial fluid pressure (IFP) is one of the forces that control this transport. A lowering of IFP in vivo results in an increased transport of fluid from the circulation into the underhydrated connective tissues, resulting in edema formation. During homeostasis, contractile connective tissue cells exert a tension on the connective tissue fibrous network by binding with β1 in-tegrins, thereby actively controlling IFP. During inflammation, the IFP is lowered but platelet-derived growth factor (PDGF)-BB induces an IFP nor-malization dependent on integrin αVβ3. We demonstrate that extracellular proteins from Streptococcus equi subspecies equi modulated cell-mediated and integrin αVβ3-directed collagen gel contraction in vitro. One of these proteins, the collagen- and fibronectin binding FNE, stimulated contraction by a process dependent on fibronectin synthesis. This study identified a pos-sible novel virulence mechanism for bacteria based on the ability of bacteria to modulate the edema response. Another protein, the collagen-binding pro-tein CNE, inhibited contraction and this led to the identification of sites in collagen monomers that potentially are involved in connecting αVβ3 to the collagen network. PDGF-BB and prostaglandin E1 (PGE1) stimulate and inhibit collagen gel contraction in vitro and normalize and lower IFP, respec-tively. We showed that these agents affected both similar and different sets of actin-binding proteins. PDGF-BB stimulated actin cytoskeleton dynamics whereas PGE1 inhibited processes dependent on cytoskeletal motor and adhesive functions, suggesting that these different activities may partly ex-plain the contrasting effects of PGE1 and PDGF-BB on contraction and IFP. Mutation of the phosphatidylinositol 3’-kinase (PI3K), but not phospholipase C (PLC)γ activation site, rendered cells unable to respond to PDGF-BB in contraction and in activation of the actin binding and severing protein cofilin. Ability to activate cofilin after PDGF-BB stimulation correlated with ability to respond to PDGF-BB in contraction, suggesting a role for cofilin in this process downstream of PDGF receptor-activated PI3K. Many proteins can modulate contraction either by affecting the extracellular matrix and cell adhesions or by altering cytoskeletal dynamics. Knowledge on how these proteins might influence IFP is likely to be of clinical importance for treat-ment of inflammatory conditions including anaphylaxis, septic shock and also carcinoma growth.
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| 93. |
- Vinter-Jensen, Lars, et al.
(författare)
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Acute contractile effects of epidermal growth factor on bladder smooth muscles. An in vivo and in vitro study in rats
- 1997
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Ingår i: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 0036-5599 .- 1651-2065. ; 31:3, s. 231-235
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Tidskriftsartikel (refereegranskat)abstract
- Chronic treatment with epidermal growth factor (EGF) stimulates growth of all wall layers of the urinary tract in pigs and rats. Herein, we investigated the acute effects of EGF on detrusor smooth muscle activity. For in vivo examination, awake rats received EGF (75 micrograms/kg) intravenously and detrusor smooth muscle activity was monitored cystometrically. The EGF bolus caused no alteration in diuresis but a doubling of the micturition frequency, a 25% increase in micturition pressures, and increased irregular baseline contractile activity. For in vitro examination detrusor smooth muscle strips were exposed to EGF (1 microgram/ml). EGF caused contraction and increase in the spontaneous activity. In conclusion, EGF increases rat detrusor smooth muscle contractile activity in vivo and in vitro. The finding suggests that a direct effect of EGF on bladder smooth muscles is part of the genesis to the growth of the detrusor smooth muscle observed after chronic EGF treatment.
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| 94. |
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| 95. |
- Wang, Bowen, et al.
(författare)
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Pharmacological and mechanical properties of isolated pig coronary veins
- 2023
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Ingår i: Frontiers in Physiology. - 1664-042X. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Recent successful cardiac transplantation from pig to non-human primates and the first pig-to-human transplantation has put the focus on the properties of the pig heart. In contrast to the coronary arteries, the coronary veins are less well characterized and the aim was to examine the mechanical and pharmacological properties of coronary veins in comparison to the arteries. Vessel segments from the left anterior descending coronary artery (LAD) and the concomitant vein were isolated from pig hearts in cardioplegia and examined in vitro. The wall thickness, active tension and active stress at optimal circumference were lower in coronary veins, reflecting the lower intravascular pressure in vivo. Reverse transcription polymerase chain reaction (RT-PCR) analysis of myosin isoforms showed that the vein could be characterized as having a slower smooth muscle phenotype compared to the artery. Both vessel types contracted in response to the thromboxane agonist U46619 with EC50 values of about 20 nM. The artery contracted in response to acetylcholine. Precontracted arteries relaxed in noradrenaline and substance P. In contrast, the veins relaxed in acetylcholine, contracted in noradrenaline and were unresponsive to substance P. In conclusion, these results demonstrate significant differences between the coronary artery and vein in the smooth muscle properties and in the responses to sympathetic and parasympathetic stimuli.
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| 96. |
- Wihlborg, Anna-Karin, et al.
(författare)
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Positive inotropic effects by uridine triphosphate (UTP) and uridine diphosphate (UDP) via P2Y(2) and P2Y(6) receptors on cardiomyocytes and release of UTP in man during myocardial infarction
- 2006
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Ingår i: Circulation Research. - 0009-7330. ; 98:7, s. 970-976
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to examine a possible role for extracellular pyrimidines as inotropic factors for the heart. First, nucleotide plasma levels were measured to evaluate whether UTP is released in patients with coronary heart disease. Then, inotropic effects of pyrimidines were examined in isolated mouse cardiomyocytes. Finally, expression of pyrimidine-selective receptors ( a subgroup of the P2 receptors) was studied in human and mouse heart, using real time polymerase chain reaction, Western blot, and immunohistochemistry. Venous plasma levels of UTP were increased (57%) in patients with myocardial infarction. In electrically stimulated cardiomyocytes the stable P2Y(2/4) agonist UTP gamma S increased contraction by 52%, similar to beta(1)-adrenergic stimulation with isoproterenol (65%). The P2Y(6)-agonist UDP gamma S also increased cardiomyocyte contraction (35%), an effect abolished by the P2Y(6)-blocker MRS2578. The phospholipase C inhibitor U73122 inhibited both the UDP beta S and the UTP gamma S-induced inotropic effect, indicating an IP3-mediated effect via P2Y(6) receptors. The P2Y(14) agonist UDP-glucose was without effect. Quantification of mRNA with real time polymerase chain reaction revealed P2Y(2) as the most abundant pyrimidine receptor expressed in cardiomyocytes from man. Presence of P2Y(6) receptor mRNA was detected in both species and confirmed at protein level with Western blot and immunohistochemistry in man. In conclusion, UTP levels are increased in humans during myocardial infarction, giving the first evidence for UTP release in man. UTP is a cardiac inotropic factor most likely by activation of P2Y(2) receptors in man. For the first time we demonstrate inotropic effects of UDP, mediated by P2Y(6) receptors via an IP3-dependent pathway. Thus, the extracellular pyrimidines ( UTP and UDP) could be important inotropic factors involved in the development of cardiac disease.
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| 97. |
- Witman, Nevin, 1982-, et al.
(författare)
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Recapitulation of developmental cardiogenesis governs the morphological and functional regeneration of adult newt hearts following injury
- 2011
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Ingår i: Developmental Biology. - : Elsevier BV. - 0012-1606 .- 1095-564X. ; 354:1, s. 67-76
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Tidskriftsartikel (refereegranskat)abstract
- Urodele amphibians, like the newt, are the champions of regeneration as they are able to regenerate many body parts and tissues. Previous experiments, however, have suggested that the newt heart has only a limited regeneration capacity, similar to the human heart. Using a novel, reproducible ventricular resection model, we show for the first time that adult newt hearts can fully regenerate without any evidence of scarring. This process is governed by increased proliferation and the up-regulation of cardiac transcription factors normally expressed during developmental cardiogenesis. Furthermore, we are able to identify cells within the newly regenerated regions of the myocardium that express the LIM-homeodomain protein Istet1 and GATA4, transcription factors found in cardiac progenitors. Information acquired from using the newt as a model organism may help to shed light on the regeneration deficits demonstrated in damaged human hearts.
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| 98. |
- Österman, Å, et al.
(författare)
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Effects of 2,3-butanedione monoxime on activation of contraction and crossbridge kinetics in intact and chemically skinned smooth muscle fibres from guinea pig taenia coli
- 1993
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Ingår i: Journal of Muscle Research and Cell Motility. - 0142-4319. ; 14:2, s. 186-194
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Tidskriftsartikel (refereegranskat)abstract
- The effects of 2,3-butanedione monoxime (BDM) were studied in smooth muscle fibres from guinea pig taenia coli. In intact muscle, active force during contractions induced by high-K+ was inhibited by about 10% in 1 mM BDM and by approximately 70% in 10 mM BDM. Intracellular [Ca2+] during contraction, measured with the fura-2 technique, was reduced in the presence of BDM. The reduction in force and [Ca2+] in the presence of 1 and 10 mM BDM could be reproduced by reduction in extracellular Ca2+, suggesting that BDM influences the Ca2+ entry or release. In skinned muscle preparations, BDM decreased the Ca2+ sensitivity of active force. This change could be explained by a decreased level of myosin light chain phosphorylation. In fibres maximally activated by thiophosphorylation, the effect of BDM on force occurred at higher concentrations; 10 mM gave no reduction of force and 60 mM 15% reduction. The maximal shortening velocity (Vmax) and force were unaffected by 30 mM BDM in thiophosphorylated muscle and decreased almost in parallel in Ca(2+)-activated contractions. The present results suggest that BDM inhibits myosin light chain phosphorylation, directly decreases force generation at the crossbridge level and inhibits the Ca2+ translocation in smooth muscle. The effect on force in skinned fibres is observed at higher BDM concentrations than those reported to be required for inhibition of force in striated muscle. The inhibition of force in intact smooth muscle could be explained by an influence on Ca2+ translocation.
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