Sustained treatment of sickle cell mice with haptoglobin increases HO-1 and H-ferritin expression and decreases iron deposition in the kidney without improvement in kidney function.

There is growing evidence that extracellular haemoglobin and haem mediate inflammatory and oxidative damage in sickle cell disease. Haptoglobin (Hp), the scavenger for free haemoglobin, is depleted in most patients with sickle cell disease due to chronic haemolysis. Although single infusions of Hp can ameliorate vaso-occlusion in mouse models of sickle cell disease, prior studies have not examined the therapeutic benefits of more chronic Hp dosing on sickle cell disease manifestations. In the present study, we explored the effect of Hp treatment over a 3-month period in sickle mice at two dosing regimens: the first at a moderate dose of 200 mg/kg thrice weekly and the second at a higher dose of 400 mg/kg thrice weekly. We found that only the higher dosing regimen resulted in increased haem-oxygenase-1 and heavy chain ferritin (H-ferritin) expression and decreased iron deposition in the kidney. Despite the decreased kidney iron deposition following Hp treatment, there was no significant improvement in kidney function. However, there was a nearly significant trend towards decreased liver infarction.

Genetic influences on the increase in blood pressure with age in normotensive subjects in Barbados.

The authors tested the single and combined effects of nuclear and mitochondrial DNA genotypes on the phenotypes of systolic blood pressure (SBP) and weight, and their changes over 5 years in normotensive subjects living in Barbados. The nuclear genotypes were gender (Y chromosome), haptoglobin (HP), and group specific component (Gc). A mitochondrial genotype was chosen as a marker for maternal lineage. Baseline clinic SBP and weight (N=78), 24-hour SBP (N=28) were measured. Five years later, clinic SBP and weight were measured again in 28 participants. Male participants generally had higher pressures than female participants. The HP genotype was associated with 5 of the 8 SBP phenotypes. The haptoglobin-1 (HP1) allele was associated with higher clinic (P=.024) and evening SBP at baseline (P=.020). The effect of HP1 appears to be dominant. Haptoglobin-2 (HP2) was associated with the increase in weight over 5 years (P=.002). Group specific component (Gc) genotype was associated with 6 of the 8 SBP phenotypes. The Gc polymorphism 2 was associated with higher 24-hour SBP, sleep SBP (midnight-6 AM), afternoon SBP (noon-6 PM) and evening SBP (6 PM to midnight). Furthermore, we found a significant association between the haptoglobin/mt-DNA and Gc/mt-DNA polymorphisms with SBP between 6 PM and midnight (P=.009 and P=.011, respectively). The 5-year changes in SBP were significantly associated with the haptoglobin/mt-DNA and Gc/mt-DNA polymorphisms (P=.005 and P=.011, respectively). Multivariate analysis for genetic effects on change in weight and change in BP suggested the rise in BP, but was not suggestive of change in weight. Furthermore, multivariate analysis was associated with Gc, but not Haptoglobin genotype. In normotensive subjects of African descent living in Barbados, the increase in blood pressure with age is significantly influenced by both nuclear and mitochondrial genotypes that are more common in African derived populations.