Heme oxygenase: protective enzyme or portal hypertensive molecule?

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Heme oxygenase: protective enzyme or portal hypertensive molecule? Richard Moreau  Journal of Hepatology  Volume 34, Issue 6, Pages 936-939 (June 2001) DOI: 10.1016/S0168-8278(01)00090-3

Fig. 1 Regulation of normal arterial smooth muscle cell (SMC) tone by the 20-kDa light chain of myosin (MLC20). In SMC, the increase and decrease in cytosolic free Ca2+ are the main mechanisms that induce contraction and relaxation, respectively. Increased Ca2+ binds to calmodulin, and the association of the Ca2+-calmodulin complex with the catalytic subunit of myosin light-chain kinase activates this enzyme to phosphorylate serine 19 of MLC20. Phosphorylation of serine 19 of MLC20 allows the myosin ATPase to be activated by actin and SMC to contract. A decrease in cytosolic free Ca2+, via a reduction in the Ca2+-calmodulin complex, inactivates myosin light-chain kinase and permits dephosphorylation of MLC20 by myosin light-chain phosphatase. These mechanisms result in deactivation of myosin ATPase and relaxation. Dephosphorylation of MLC20 causes desensitization of the contractile apparatus to Ca2+. Journal of Hepatology 2001 34, 936-939DOI: (10.1016/S0168-8278(01)00090-3)

Fig. 2 Molecular mechanisms for cyclic GMP-induced relaxation in normal arterial smooth muscle cells. Cyclic GMP (probably via the activation of PKGIα) induces relaxation by decreasing [Ca2+]i and desensitizing the contractile apparatus to Ca2+. Cyclic GMP decreases [Ca2+]i by inhibiting L-type Ca2+-channels (and reducing the entry of extracellular Ca2+). cGMP-induced L-type Ca2+-channel inhibition may be direct or indirect (via SMC membrane hyperpolarization). Membrane hyperpolarization may result from activation of large-conductance, Ca2+-activated K+ (BKCa) channels or of the Na+-K+ ATPase. Cyclic GMP also decreases [Ca2+]i by inducing Ca2+ extrusion and sequestration (via stimulation of Ca2+-ATPases located in the plasma membrane and the membrane of the sarcoplasmic reticulum, respectively). Cyclic GMP decreases [Ca2+]i by reducing the mobilization of intracellular Ca2+ (by inhibiting the production of inositol trisphosphate (InsP3) due to the activation of the heterotrimeric G protein (G)/phospholipase C (PLC) signalling pathway). Finally, cyclic GMP may also decrease InsP3–induced mobilization of intracellular Ca2+ by inhibiting the InsP3 receptor which is in the membrane of the sarcoplasmic reticulum. On the other hand, cyclic GMP desensitizes the contractile apparatus to Ca2+ by activating myosin light-chain phosphatase, resulting in MLC20 dephosphorylation (see Fig. 1, caption). The plus sign means activation by cyclic GMP; the minus sign means inhibition by cyclic GMP. Journal of Hepatology 2001 34, 936-939DOI: (10.1016/S0168-8278(01)00090-3)