ExActa: blood pressure

High blood pressure plays a prominent role in the development of cardiovascular disease such as stroke and myocardial infarction. On the other hand, low blood pressure may also predict cardiovascular disease risk in subpopulations such as haemodialysis patients (Anker et al. 2016) according to a recent study in almost 5000 patients in a European cohort. In the past, researchers focused typically on knockout models when addressing genetic alterations in animals. It might be evident that fine-tuning and imbalanced gene regulation is of great importance too, but it is difficult to address. These aspects would include, for example, mechanisms that modify transcriptional and translational activity, splicing and post-translational mechanisms such as folding, protein modification, storage and other processing. These mechanisms might be determined genetically but also by non-genetic epigenetic factors. An example of a genetically determined modification found in a noncoding region is a single nucleotide polymorphism (SNP) that increases the FOXA2-bound enhancer activity and increases the risk of another complex condition, namely type II diabetes, which was observed in a ‘brute force-like’ fine mapping approach (Gaulton et al. 2015). Non-coding RNA might also contribute to gene regulation, and SNPs therein may confer increased susceptibility to the development of high blood pressure as it was suggested for the non-coding RNA CDKN2B-AS1 (Bayoglu et al. 2016). The cardiovascular system is one of the most addressed systems in modern pharmaceutical therapies. A number of feedback mechanisms are involved in the regulation of the arterial blood pressure. The regulation of blood pressure is therefore complex, and if one of the systems is out of balance, others may take a greater role. A number of interesting articles appeared in recent issues of Acta Physiologica dealing with the regulation of blood pressure at various levels; some of them include aspects of gene regulation. Knockout models are used extensively in cardiovascular research. The genetic background of the animal strain may greatly modify the phenotype. This may explain in part conflicting results in knockout studies in general. This issue was addressed by Kim et al. (2015) for the A1AR deficiency on cardiovascular and renal functional parameters. The A1 adenosine receptor (A1AR) has been proposed to be important in the tubuloglomerular feedback (TGF) as determined by stop-flow pressure measurements. The authors investigated blood pressure and heart rate and plasma renin concentrations and TGF for homozygous A1AR deficiency in the C57Bl/6 and SWR/J background. The authors find that a high NaCl intake increased arterial pressure in A1AR / mice on C57Bl/6 background, while there was less or no salt sensitivity in the SWR/J background. Plasma renin activity was not altered by A1AR deficiency in any of the investigated strains. The TGF was found to be absent in A1AR-deficient mice with SWR/J genetic background. Salt sensitivity of blood pressure is one of the enigmas in the field and may depend on ethnic background in humans (Farquhar et al. 2015). In a study conducted by Isaksson et al. (2014), the relation between plasma renin concentration, arterial blood pressure and glomerular filtration rate (GFR) depending on sodium intake was addressed in a rat model. The authors find a markedly log-linear relationship between the entities; for example, an increase in sodium intake by a factor of 10 was followed by a blood pressure increase by 5 mmHg and GFR increase by 1.4 mL min . Surprisingly, under steady state conditions plasma renin levels appear independent of renal nerves in this model, as shown by pharmacological intervention and denervation experiments. Khan et al. (2015) found that intact renal nerves are required for the following: feeding a high-fat diet causes hypertension associated with dysregulation of the arterial and cardiopulmonary baroreflexes in rats. They conclude that in obese states, neural signals arising from the kidney may contribute to a deranged autonomic control (Khan et al. 2015). Hypoxia is a key event in development of vascular beds in the normal development and also under pathological conditions such as tumour growth and is governed by gene regulatory mechanisms. The effect of high-altitude-induced hypoxia on blood pressure was investigated in humans by Calbet et al. (2014). The authors find an increase of arterial blood pressure by 13% at an altitude of about 4500 m above sea level. Vasodilatory responses after infusion of adenosine and ATP were reduced in high altitude, which might contribute to the effect of higher blood pressure. An interesting study towards the establishment of urinary proteomic biomarkers for essential hypertension was conducted by Damkjaer et al. (2014). An intrarenal mechanism important for sodium balance