Atrial natriuretic peptide is negatively regulated by microRNA-425

Numerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that the variant rs5068 (A/G) in the 3′ untranslated region of NPPA, the gene encoding atrial natriuretic peptide (ANP), is associated with blood pressure. We selected individuals on the basis of rs5068 genotype (AG vs. AA) and fed them a low- or high-salt diet for 1 week, after which they were challenged with an intravenous saline infusion. On both diets, before and after saline administration, ANP levels were up to 50% higher in AG individuals than in AA individuals, a difference comparable to the changes induced by high-salt diet or saline infusion. In contrast, B-type natriuretic peptide levels did not differ by rs5068 genotype. We identified a microRNA, miR-425, that is expressed in human atria and ventricles and is predicted to bind the sequence spanning rs5068 for the A, but not the G, allele. miR-425 silenced NPPA mRNA in an allele-specific manner, with the G allele conferring resistance to miR-425. This study identifies miR-425 as a regulator of ANP production, raising the possibility that miR-425 antagonists could be used to treat disorders of salt overload, including hypertension and heart failure.     

Mast cell heterogeneity: evidence that mast cells isolated from various connective tissue locations in the rat display markedly graded phenotypes.

The present study has extended histochemical and functional investigations into rat mast cell heterogeneity using isolated mast cells from four connective tissue locations; the peritoneum, mesentery, lung and skin. On histological examination, mast cells from these locations displayed a range of phenotypes following formalin fixation and staining with Alcian blue/safranin O, suggesting the existence of both chondroitin sulphate and heparin proteoglycans in varying proportions in these cell types. Functional studies using the structurally diverse polycationic secretagogues, compound 48/80, the polyamino acids, polymyxin B, substance P, ACTH1-24, mastoparan, protamine sulphate, histone, d-tubocurarine and ranitidine confirmed the existence of such phenotypic gradation. This investigation highlights the inappropriate usage of the terms CTMC and MMC which represent two phenotypic extremes between which a gradation of phenotypes clearly exists.     

Genetic modifiers of hypertension in soluble guanylate cyclase α1-deficient mice

Nitric oxide (NO) plays an essential role in regulating hypertension and blood flow by inducing relaxation of vascular smooth muscle. Male mice deficient in a NO receptor component, the α1 subunit of soluble guanylate cyclase (sGCα1), are prone to hypertension in some, but not all, mouse strains, suggesting that additional genetic factors contribute to the onset of hypertension. Using linkage analyses, we discovered a quantitative trait locus (QTL) on chromosome 1 that was linked to mean arterial pressure (MAP) in the context of sGCα1 deficiency. This region is syntenic with previously identified blood pressure-related QTLs in the human and rat genome and contains the genes coding for renin. Hypertension was associated with increased activity of the renin-angiotensin-aldosterone system (RAAS). Further, we found that RAAS inhibition normalized MAP and improved endothelium-dependent vasorelaxation in sGCα1-deficient mice. These data identify the RAAS as a blood pressure-modifying mechanism in a setting of impaired NO/cGMP signaling.     

Acral gangrene attributed to calcific azotaemic arteriopathy and the steal effect of an arteriovenous fistula

We describe a young male non-smoker who developed acral gangrene within 4 months of commencing haemodialysis. Amputation of the left hand proximal to the wrist was ultimately required. The onset of peripheral gangrene in this dialysis patient is attributed to calcific azotaemic arteriopathy and the steal effect of an arteriovenous fistula.