The natriuretic peptide system includes three known peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuret

Background and Purpose— A precise definition of genetic factors responsible for common forms of stroke is still lacking. The purpose of the present study was to investigate the contributory role of the genes encoding atrial natriuretic peptide ( ANP ) and type A natriuretic peptide receptor ( NPRA ) in humans’ susceptibility to develop ischemic stroke. Methods— Allele and genotype frequencies of ANP and NPRA were characterized in an Italian case-control study with patients affected by vascular disease or risk factors. Subjects were recruited from the island of Sardinia (206 cases, 236 controls). Results— A significant association between the ANP /TC2238 polymorphic site and stroke occurrence was found when a recessive model of inheritance was assumed. The risk conferred by this mutant genotype, when estimated by multivariate logistic regression analysis, was 3.8 (95% confidence interval, 1.4 to 10.9). A significantly increased risk of stroke recurrence was observed among cases carrying the ANP /CC2238 genotype compared with cases carrying the ANP /TT2238 genotype ( P =0.04). No direct association of NPRA with stroke occurrence was detected. However, a significant epistatic interaction between the ANP /CC2238 genotype and an allelic variant of NPRA led to a 5.5-fold increased risk of stroke (95% confidence interval, 1.5 to 19.4). Conclusions— Our findings support a direct contributory role of ANP to stroke in humans. A significant interaction between ANP and NPRA on stroke occurrence was found.

Epigenetics is the branch of molecular biology that studies modifications able to change gene expression without altering the DNA sequence. Epigenetic modulations include DNA methylation, histone modifications, and noncoding RNAs. These gene modifications are heritable and modifiable and can be triggered by lifestyle and nutritional factors. In recent years, epigenetic changes have been associated with the pathogenesis of several diseases such as diabetes, obesity, renal pathology, and different types of cancer. They have also been related with the pathogenesis of cardiovascular diseases including ischemic stroke. Importantly, since epigenetic modifications are reversible processes they could assist with the development of new therapeutic approaches for the treatment of human diseases. In the present review article, we aim to collect the most recent evidence concerning the impact of epigenetic modifications on the pathogenesis of ischemic stroke in both animal models and humans.

The stroke-prone spontaneously hypertensive rat (SHRsp) represents an animal model of increased susceptibility to high-salt diet–induced cerebral and renal vascular injuries. High blood pressure and genetic factors are viewed as major contributing factors. In high-salt–loaded SHRsp and stroke-resistant SHR animals, we determined blood pressure levels, degree of kidney lesions, renal uncoupling protein 2 (UCP2) gene and protein expression levels along with rattus norvegicus (rno)-microRNA (miR) 24 and 34a gene expression, nuclear factor-κB protein levels, and oxidative stress. In vitro, UCP2 gene silencing was performed in renal mesangial cells. We found more severe degree of renal damage in SHRsp at the end of 4-week high-salt dietary treatment as compared with stroke-resistant SHR, despite comparable blood pressure levels, along with increased rate of inflammation and oxidative stress. Kidney UCP2 gene and protein expression levels were significantly downregulated under high-salt diet in SHRsp, but not in stroke-resistant SHR. Differential UCP2 regulation was paralleled by differential expression of kidney rno-miR 24 and 34a, known to target UCP2 gene, in the 2 strains. UCP2 gene silencing in renal mesangial cells led to increased rate of reactive oxygen species generation, increased inflammation and apoptosis, reduced cell vitality, and increased necrosis. In conclusion, high-salt diet downregulates the antioxidant UCP2-dependent mechanism in kidneys of SHRsp, but not of stroke-resistant SHR. A parallel differential kidney miR regulation under high-salt diet in the 2 strains may contribute to the differential UCP2 modulation. UCP2 is a critical protein to prevent oxidative stress damage in renal mesangial cells in vitro.