Nitric oxide (NO) is an important vasodilator with a well-established role in cardiovascular homeostasis. While mediator is synthesized from L-arginine by neuronal, endothelial, and inducible nitric oxide synthases (NOS1,NOS3 and NOS2 respectively), NOS3 is the most important isoform for NO formation in the cardiovascular system. NOS3 is a dimeric enzyme whose expression and activity are regulated at transcriptional, posttranscriptional,and posttranslational levels. The NOS3 gene, which encodes NOS3, exhibits a number of polymorphic sites including single nucleotide polymorphisms (SNPs), variable number of tandem repeats (VNTRs), microsatellites, and insertions/deletions. Some NOS3 polymorphisms show functional effects on NOS3 expression or activity, thereby affecting NO formation. Interestingly, many studies have evaluated the effects of functional NOS3 polymorphisms on disease susceptibility and drug responses. Moreover, some studies have investigated how NOS3 haplotypes may impact endogenous NO formation and disease susceptibility. In this article,we carried out a comprehensive review to provide a basic understanding of biochemical mechanisms involved in NOS3 regulation and how genetic variations in NOS3 may translate into relevant clinical and pharmacogenetic implications.

Hypertension is a multifactorial disease that affects approximately one billion subjects worldwide and is a major risk factor associated with cardiovascular events, including coronary heart disease and cerebrovascular accidents. Therefore, adequate blood pressure control is important to prevent these events, reducing premature mortality and disability. However, only one third of patients have the effective control of blood pressure, despite several classes of antihypertensive drugs available. These disappointing outcomes may be at least in part explained by interpatient variability in drug response due to genetic polymorphisms. To address the effects of genetic polymorphisms on blood pressure responses to the antihypertensive drug classes, studies have applied candidate genes and genome wide approaches. More recently, a third approach that considers gene-gene interactions has also been applied in hypertension pharmacogenomics. In this article, we carried out a comprehensive review of recent findings on the pharmacogenomics of antihypertensive drugs, including diuretics, β-blockers, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, and calcium channel blockers. We also discuss the limitations and inconsistences that have been found in hypertension pharmacogenomics and the challenges to implement this valuable approach in clinical practice.

Nitric oxide (NO) is an important vasodilator produced by vascular endothelium. Its enzymatic formation is derived from three different synthases: neuronal (nNOS), endothelial (eNOS) and inducible (iNOS) synthases. While relatively small amounts of NO produced by eNOS are important to cardiovascular homeostasis, high NO levels produced associated with iNOS activity may have detrimental consequences to the cardiovascular system and contribute to hypertension. In this article, we reviewed current literature and found mounting evidence indicating that increased iNOS expression and activity contribute to the pathogenesis of hypertension and its complications. Excessive amounts of NO produced by iNOS up-regulation can react with superoxide anions forming peroxynitrite, thereby promoting nitrosative stress and endothelial dysfunction. In addition, abnormal iNOS activity can up-regulate arginase activity, allowing it to compete with eNOS for L-arginine, thereby resulting in reduced NO bioavailability. This may also lead to eNOS uncoupling with enhanced production of superoxide anions instead of NO. All these alterations mediated by iNOS apparently contribute to hypertension and its complications. We also reviewed current evidence showing the effects of iNOS inhibitors on different animal models of hypertension. iNOS inhibition apparently exerts antihypertensive effects, decreases oxidative and nitrosative stress, and improves vascular function. Together, these studies highlight the possibility that iNOS is a potential pharmacological target in hypertension.

Protein kinase C (PKC) signalling is critically involved in the control of blood pressure. Angiotensin-converting enzyme inhibitors (ACEi) affect PKC expression and activity, which are partially associated with the responses to ACEi. We examined whether PRKCA (protein kinase C, alpha) polymorphisms (rs887797 C>T, rs1010544 T>C and rs16960228 G>A), or haplotypes, and gene-gene interactions within the ACEi pathway affect the antihypertensive responses in 104 hypertensive patients treated with enalapril as monotherapy. Patients were classified as poor responders (PR) or good responders (GR) to enalapril if their changes in mean arterial pressure were lower or higher than the median value, respectively. Multi-factor dimensionality reduction was used to characterize interactions among PRKCA, NOS3 (nitric oxide synthase 3) and BDKRB2 (bradykinin receptor B2) polymorphisms. The TC+CC genotypes for the rs1010544 polymorphism were more frequent in GR than in PR (p = 0.037). Conversely, the GA+AA genotypes for the rs16960228 polymorphism, and the CTA haplotype, were more frequent in PR than in GR (p = 0.040 and p = 0.008, respectively). Moreover, the GG genotype for the PRKCA rs16960228 polymorphism was associated with PR or GR depending on the genotypes for the rs2070744 (NOS3) and rs1799722 (BDKRB2) polymorphisms (p = 0.012). Our results suggest that PRKCA polymorphisms and gene-gene interactions within the ACEi pathway affect the antihypertensive responses to enalapril.

Nitric oxide (NO) is a vasoactive substance synthesized from l-arginine by neuronal (NOS1), endothelial (NOS3), and inducible (NOS2) nitric oxide synthases. NOS3 is the most important NO synthase isoform in the vascular endothelium and therefore it exerts critical roles in the cardiovascular system. NOS3 is encoded by NOS3 gene, which displays a large number of genetic polymorphisms such as single nucleotide polymorphisms (SNPs), variable number of tandem repeats (VNTRs), microsatellites, and insertions/deletions. Interestingly, NOS3 regulation and NO production are affected by some NOS3 polymorphisms. Given these functional consequences and the protective role of NOS3 against cardiovascular diseases, many studies have investigated whether NOS3 polymorphisms affect the susceptibility to cardiovascular diseases and the responses to drugs that affect NOS3 activity in the cardiovascular system. In addition, a growing body of evidence shows the effects of combinations of NOS3 polymorphisms within haplotype blocks on NO bioavailability and disease susceptibility. In this review, we discuss the basic biochemical mechanisms of NOS3 regulation and the clinical and pharmacogenetic impact of NOS3 polymorphisms on cardiovascular diseases.

Proton pump inhibitors (PPIs) are widely used drugs that may increase the cardiovascular risk by mechanisms not entirely known. While PPIs increase asymmetric dimethylarginine (ADMA) levels and inhibit nitric oxide production, it is unknown whether impaired vascular redox biology resulting of increased xanthine oxidoreductase (XOR) activity mediates PPIs-induced endothelial dysfunction (ED). We examined whether increased XOR activity impairs vascular redox biology and causes ED in rats treated with omeprazole. We also examined whether omeprazole aggravates the ED found in hypertension. Treatment with omeprazole reduced endothelium-dependent aortic responses to acetylcholine without causing hypertension. However, omeprazole did not aggravate two-kidney, one-clip (2K1C) hypertension, nor hypertension-induced ED. Omeprazole and 2K1C increased vascular oxidative stress as assessed with dihydroethidium (DHE), which reacts with superoxide, and by the lucigenin chemiluminescence assay. The selective XOR inhibitor febuxostat blunted both effects induced by omeprazole. Treatment with omeprazole increased plasma ADMA concentrations, XOR activity and systemic markers of oxidative stress. Incubation of aortic rings with ADMA increased XOR activity, DHE fluorescence and lucigenin chemiluminescence signals, and febuxostat blunted these effects. Providing functional evidence that omeprazole causes ED by XOR-mediated mechanisms, we found that febuxostat blunted the ED caused by omeprazole treatment. This study shows that treatment with omeprazole impairs the vascular redox biology by XOR-mediated mechanisms leading to ED. While omeprazole did not further impair hypertension-induced ED, further studies in less severe animal models are warranted. Our findings may have major relevance, particularly to patients with cardiovascular diseases taking PPIs.

AIF1 limits necrotic core expansion in atherosclerotic lesions.• AIF1 supports macrophage survival and efferocytotic activities.• AIF1 promotes NF-κB pathway activity in macrophages.• AIF1 induces NF-κB-dependent stress response, inflammatory, and anti-apoptotic gene expression in macrophages.• AIF1 promotes NF-κB pathway and limits apoptosis in atherosclerotic lesions in vivo.

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