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Background Essential hypertension results from the interaction of several genetic and environmental factors. Identification of genetic factors that smodulate blood pressure (BP) response to interventions can lead to improved strategies for prevention and control. The purpose of this study was to identify genes that modulate BP response to dietary interventions. Methods We used data and samples collected in two randomized feeding studies to determine the extent to which genetic architecture is associated with the effect on BP of sodium intake and the Dietary Approaches to Stop Hypertension (DASH) dietary pattern. Participants in both trials were adults with above-optimal BP or unmedicated stage 1 hypertension. Genomic DNA was typed forseveral candidate genes. Results The effect of sodium intake on BP differed by genotype at the angiotensinogen, β2-adrenergic receptor, and kallikrein loci. The effect of DASH dietary pattern on BP differed by genotype at the β2-adrenergic receptor locus. Conclusions These findings have implications for understanding the mechanism(s) through which diet affects BP, the heterogeneity of these effects, and the extent to which dietary interventions can modulate genetic predisposition. American Journal of Hypertension, advance online publication 18 November 2010;. doi:10.1038/ajh.2010.223

Angiotensinogen (AGT) is the sole precursor of all angiotensin peptides. Although AGT is generally considered as a passive substrate of the renin-angiotensin system, there is accumulating evidence that the regulation and functions of AGT are intricate. Understanding the diversity of AGT properties has been enhanced by protein structural analysis and animal studies. In addition to whole-body genetic deletion, AGT can be regulated in vivo by cell-specific procedures, adeno-associated viral approaches and antisense oligonucleotides. Indeed, the availability of these multiple manipulations of AGT in vivo has provided new insights into the multifaceted roles of AGT. In this review, the combination of structural and functional studies is highlighted to focus on the increasing recognition that AGT exerts effects beyond being a sole provider of angiotensin peptides.

The renin-angiotensin-aldosterone system (RAAS) is important for the development of hypertension, and several antihypertensive drugs target this system. Our aim was to determine whether specific single nucleotide polymorphisms (SNPs) in RAAS genes were related to the blood pressure (BP) lowering effect of antihypertensive treatment. Patients with mild to moderate primary hypertension and left ventricular hypertrophy were randomized in a double-blind fashion to treatment with either the angiotensin II type 1 receptor antagonist irbesartan ( n = 48) or the β 1-adrenergic receptor blocker atenolol ( n = 49) as monotherapy. A microarray-based minisequencing system was used to genotype 30 SNPs in seven genes in the RAAS. These polymorphisms were related to the antihypertensive response after 12 weeks treatment. The BP reductions were similar in the atenolol and the irbesartan groups. Presence of the angiotensinogen (AGT) -6A allele or the AGT 235T allele were both associated with the most pronounced systolic BP response to atenolol treatment ( P = .001 when -6 AA+AG was compared with GG and P = .008 for presence of the 235T variant compared with 235 MM). We found that SNPs in the angiotensinogen gene were associated with the BP lowering response to atenolol. This study is limited by a relatively small sample size, and the results should therefore be viewed as preliminary. Despite this limitation, these results illustrate the potential of using SNP genotyping as a pharmacogenetic tool in antihypertensive treatment.

Background Polymorphisms in genes coding for components of the renin–angiotensin system (RAS) and α-adducin (ADD1) have been reported to be associated with blood pressure (BP) responses to antihypertensive agents. The results, however, have not been consistent and most of the earlier studies have been small and lacked placebo-control. Therefore, the association of common polymorphisms in these genes with BP responses to four different antihypertensive drugs was analyzed in a controlled study. Methods The study included 208 hypertensive Finnish men from the GENRES study. All of them used amlodipine 5 mg, bisoprolol 5 mg, hydrochlorothiazide (HCT) 25 mg, and losartan 50 mg daily, each for 4 weeks as a monotherapy in a double-blind, randomized, study. The treatment periods were separated by 4-week placebo periods. Both 24-h ambulatory (ABP) and office BP (OBP) measurements were carried out. The polymorphisms analyzed were ADD1 Gly460Trp, angiotensinogen (AGT) Met235Thr, angiotensin converting enzyme (ACE) insertion/deletion (I/D), and angiotensin II type 1 receptor (AGTR1) 1166A/C. Results The presence of 460Trp allele of ADD1, previously suggested to be a marker of thiazide responsiveness, did not predict a better response to HCT. There was no significant association of AGT Met235Thr, ACE I/D, and AGTR1 1166A/C polymorphisms with BP responses to the study drugs. ADD1 460Trp and AGT 235Thr alleles were associated with higher systolic white coat effect (WCE) during the placebo periods (P values 0.03 and 0.01, respectively). Conclusions Common polymorphisms of ADD1, AGT, ACE, and AGTR1 do not markedly predict BP responses to amlodipine, bisoprolol, HCT, and losartan, at least in white hypertensive men.

Nature Medicine explores the latest translation and clinical research news, with results from a phase 2 clinical trial of zilebesiran from Alnylam and Roche. Nature Medicine explores the latest translation and clinical research news, with results from a phase 2 clinical trial of zilebesiran from Alnylam and Roche. Image credit: Denis Pobytov / DigitalVision Vectors / Getty

Angiotensinogen plays an essential role in maintaining circulatory homeostasis. AGT rs5050(T > G) has been identified as a regulator of the transcription of AGT mRNA, with differential expression between sexes. We sought to determine if rs5050(T > G), an estrogen response element, modifies the relationship between estrogen and angiotensinogen levels. rs5050(T > G) was genotyped, and plasma angiotensinogen levels were measured in 4,831 MESA participants, including postmenopausal women, on hormone therapy (n = 709) or not (n = 1,551), and 2,581 men. Linear regression models were employed to determine the associations of angiotensinogen with rs5050(T > G) allele dosage; and to evaluate whether rs5050(T > G) modifies the association between estradiol and angiotensinogen, with a main effect term and interaction term between rs5050(T > G)*estradiol. Estimated marginal means (EMMs) were used to further evaluate the effect of estradiol on angiotensinogen across different rs5050 alleles (T > G). rs5050TT had the highest median levels of angiotensinogen, followed by TG and GG. Adjusted main effect model showed positive associations between estradiol and angiotensinogen, with each rs5050T allele associated with 0.329 SD higher log-angiotensinogen levels (CI 95% 0.293, 0.365). The interaction rs5050(T > G)*estradiol was not significant, with EMMs exhibiting overlapping slope confidence intervals across genotypes. The proportion of the variance in angiotensinogen explained by modeling increases from 47.9% to 51.6% when including rs5050(T > G) or interation rs5050(T > G)*estradiol in the model. rs5050(T > G) is associated with circulating angiotensinogen levels, but rs5050(T > G) alleles do not influence the relationship between estradiol and angiotensinogen. This suggests that estrogen's effect on angiotensinogen regulation occurs independently of rs5050(T > G), despite its location within an estrogen-responsive element.

Background Essential hypertension (EH) is a complex disorder influenced by a combination of genetic and environmental factors. The renin-angiotensin system (RAS), particularly the angiotensinogen (AGT) gene, plays a crucial role in blood pressure regulation. While previous studies have implicated AGT gene polymorphisms in EH risk, their impact on the Iranian population remains relatively unexplored. Objective To investigate the association between common variants of the AGT gene and their haplotypes with EH in a large cohort of Iranian individuals. Methods This nested case-control study utilized data from the Tehran Cardiometabolic Genetic Study (TCGS), encompassing 6,100 adults (3,217 cases with EH and 2,883 controls). Eleven Single Nucleotide Polymorphisms (SNPs) within the AGT gene were genotyped. Logistic regression models, adjusted for age, sex, and Body Mass Index (BMI), were employed to assess the association between SNPs and EH. Haplotype analysis was conducted to evaluate the combined effects of multiple SNPs. Results In a univariate analysis, eight of the eleven SNPs had strong links to EH. Logistic regression analysis showed that certain alleles of rs2493141, rs2004776, and especially rs2493151 were linked to a higher risk of EH. Even after taking BMI into account, rs2493151 remained significant. Four haplotypes were found to be significantly linked to the risk of EH through haplotype analysis. Conclusion This study provides evidence for the involvement of AGT gene variants and haplotypes in the pathogenesis of EH in the Iranian population. These findings highlight the importance of considering genetic factors in the development and management of this prevalent condition.

Zilebesiran represents an innovative antihypertensive therapy employing small interfering RNA (siRNA) to inhibit hepatic angiotensinogen, a key regulator of the renin–angiotensin–aldosterone system. By directly targeting the source of angiotensin II production, zilebesiran offers a novel mechanism distinct from conventional antihypertensive treatments. In the clinical studies KARDIA-1 and KARDIA-2, zilebesiran demonstrated clinically significant reductions in systolic blood pressure, with effects lasting up to 24 weeks after a single subcutaneous injection. In KARDIA-1, doses of 300 mg and 600 mg administered every 6 months resulted in reductions of over 15 mmHg in systolic blood pressure at 3 months compared with placebo. KARDIA-2 further showed an additional reduction of up to 12.1 mmHg at 3 months when zilebesiran was used as an adjunct to standard antihypertensive therapy. KARDIA-3 is currently evaluating the therapy in a larger global population to assess its impact on major cardiovascular outcomes. Zilebesiran has demonstrated a favorable safety profile with minimal adverse events, offering potential advantages for patients with resistant or uncontrolled hypertension and those at high cardiovascular risk, especially where adherence to daily oral medications is challenging. Beyond blood pressure reduction, zilebesiran may protect target organs, including the heart, kidneys, and retina. In conclusion, zilebesiran represents a promising siRNA-based therapy that may redefine the management of difficult-to-control hypertension, offering durable, targeted, and patient-friendly treatment with broad cardiovascular benefits. Future studies will clarify its long-term safety, efficacy across diverse populations, and integration into personalized hypertension management strategies.

Preeclampsia, with the hallmark features of new-onset hypertension and proteinuria after 20 weeks of gestation, is a major cause of fetal and maternal morbidity and mortality. Studies have demonstrated a role for the renin-angiotensin system (RAS) in its pathogenesis; however, small-molecule RAS blockers are contraindicated because of fetal toxicity. We evaluated whether siRNA targeting maternal hepatic angiotensinogen (Agt) could ameliorate symptoms of preeclampsia without adverse placental or fetal effects in 2 rodent models. The first model used a cross of females expressing human Agt with males expressing human renin, resulting in upregulation of the circulating and uteroplacental RAS. The second model induced ischemia/reperfusion injury and subsequent local and systemic inflammation by surgically reducing placental blood flow mid-gestation (reduced uterine perfusion pressure [RUPP]). These models featured hypertension, proteinuria, and fetal growth restriction, with altered biomarkers. siRNA treatment ameliorated the preeclamptic phenotype in both models, reduced blood pressure, and improved intrauterine growth restriction, with no observed deleterious effects on the fetus. Treatment also improved the angiogenic balance and proteinuria in the transgenic model, and it reduced angiotensin receptor activating antibodies in both. Thus, an RNAi therapeutic targeting Agt ameliorated the clinical sequelae and improved fetal outcomes in 2 rodent models of preeclampsia.

Diabetic cardiomyopathy is a cascade of complex events leading to eventual failure of the heart and cardiac fibrosis being considered as one of its major causes. miR‐133a is one of the most abundantly expressed microRNAs in the heart. We investigated the role of miR‐133a during severe hyperglycaemia. And, our aim was to find out what role miR‐133a plays during diabetes‐induced cardiac fibrosis. We saw a drastic decrease in miR‐133a expression in the hearts of streptozotocin‐induced diabetic animals, as measured by RT‐qPCR. This decrease was accompanied by an increase in the transcriptional co‐activator EP300 mRNA and major markers of fibrosis [transforming growth factor‐β1, connective tissue growth factor, fibronectin (FN1) and COL4A1]; in addition, focal cardiac fibrosis assessed by Masson's trichome stain was increased. Interestingly, in diabetic mice with cardiac‐specific miR‐133aa overexpression, cardiac fibrosis was significantly decreased, as observed by RT‐qPCR and immunoblotting of COL4A1, ELISA for FN1 and microscopic examination. Furthermore, Cardiac miR‐133a overexpression prevented ERK1/2 and SMAD‐2 phosphorylation. These findings show that miR‐133a could be a potential therapeutic target for diabetes‐induced cardiac fibrosis and related cardiac dysfunction.