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  • BQ-788 sodium salt sale To prevent toxicity of free hemoglob

    2021-10-21

    To prevent toxicity of free hemoglobin as well as its degradation metabolites heme and free iron, several scavenger proteins and degradation enzymes protect the body. Haptoglobin (Hp) is the most well described hemoglobin scavenging protein that binds free hemoglobin and transports it to macrophages and hepatocytes where the uptake is facilitated by CD163 receptor-mediated BQ-788 sodium salt sale [15]. In the intracellular compartment of primarily macrophages hemoglobin is degraded to heme in the lysosomes and then furthermore catabolized by the rate limiting enzyme heme oxygenase 1 (HO-1) to biliverdin, carbon monoxide (CO) and free iron [16]. Biliverdin is reduced to bilirubin which is excreted via the bile system. Carbon monoxide relaxes the smooth muscle layer of vessels causing a vasodilatating effect that lowers the blood pressure [17]. Yet another heme scavenger is α1-microglobulin (A1M) a lipocalin protein, that in addition to heme also binds radicals and has enzymatic reducing capacity. Recently, A1M has been shown to be up-regulated in early [12], [13] and late onset PE [11], [14] as well as having therapeutic properties in several PE animal models [18]. Hemopexin (Hx) is a circulating plasma glycoprotein mainly synthesized in the liver. It acts as an acute phase reactant and binds free heme with high affinity [19], [20]. The heme affinity of Hx is affected by several factors, such as decreased pH, reducted state of the heme iron atom, binding of nitric oxide (NO) to the heme iron or the presence of chloride anions and divalent metal ions [17]. Sodium cations increase heme affinity to Hx [17]. The Hx-heme complex is transported to macrophages and hepatocytes expressing the LDL receptor-related protein 1 (LRP1), which facilitates uptake of the Hx-heme complex [21]. In this way Hx serves a backup system to Hp. When the Hp-system is overwhelmed, Hx clears the blood from free heme [17]. Hemopexin has in fact been shown to prevent endothelial damage in a mouse model [22]. Hemopexin also has serine protease activity [23]. This enzymatic activity can be measured by a method described by Bakker et al. [23], [24]. Data from in vitro studies showed a down-regulating effect by Hx activity on the renin-angiotensin system (RAS). Hemopexin activity was shown to down-regulate the angiotensin II receptor in monocytes, endothelial cells, and rat aortic rings [25]. Therefore, the Hx activity has been suggested as a regulator of the vascular responsiveness to angiotensin II [26]. This suggestion is in line with the fact, that Hx activity in normal pregnancy is described to increase from 10 weeks of gestation onwards [25], and could be an explanation to the decreasing angiotensin II sensitivity in pregnancy. Moreover, during PE the Hx activity is decreased and the vascular angiotensin II sensitivity consequently increased [25].
    Materials and methods
    Results
    Discussion The results complement the recently published study in which decreased levels of haptoglobin were shown in PE patients. The heme scavenger A1M was in contrast, shown to be up-regulated in early onset [12], [13] and late onset PE [11], [14]. In concordance with previous findings, a decreased Hx activity has been shown in patients with manifest PE [24]. Interestingly, the present result showed that the Hx activity was significantly decreased in patients with late-onset PE only, although previous studies have shown plasma Hx activity to be significantly decreased in early onset PE [24]. The main reason for this discrepancy could be the present study set-up; early onset patients were compared with term controls, while in the previous study, gestational age matched controls were used. If instead gestational age matched controls had been used the results might have been more in line with previous studies [24]. The set-up is clearly a limitation for the present study and will have to be confirmed in a study with controls matched for gestational age. In the perfect world, all samples should be transferred to multiples of the median (MOM) values. In the given study, however we did not have the needed number of controls to establish a median and normal range according to gestational age. The findings therefore need to be validated in a larger cohort.