Myocardin gene regulatory variants as surrogate markers of cardiac hypertrophy - study in a genetically homogeneous population.

Myocardin is thought to contribute to heart hypertrophy as assessed in animal models. The aim of this study was to identify polymorphisms on the myocardin gene and investigate possible relationships with left ventricular structure in human hypertrophic cardiomyopathy (HCM). Eighty-four native Cretan individuals (36 patients with HCM and 48 healthy controls) were examined by direct sequencing and subsequent restriction fragment length polymorphism analysis and six polymorphisms were identified in the promoter region at positions -435T>C (rs758187), -629A>T (rs8071072), -1030C>G (rs1233851), -1069A>G, -1166A>G and -1406G>A (rs976906). Allele and haplotype frequencies were not significantly different between patients and controls. However, patients carrying the [-435C;-629T] allelic variant had decreased left ventricular wall thickness (LVWT, p = 0.020) and left ventricular mass (p = 0.006) as compared with the wild-type genotype. Carrier status of this myocardin promoter allelic variant was also associated with significant lower myocardin mRNA levels in peripheral blood (p = 0.039). Thus, a myocardin promoter allelic variant existing in the normal Cretan population was associated with decreased left ventricular mass in HCM patients and decreased myocardin mRNA levels in peripheral blood. Our results may be limited by the limited sample size, but are strengthened by the genetic homogeneity of the Cretan population. Our data suggest that functional natural myocardin promoter variation might be a genetic factor contributing to inter-individual differences in the development of cardiac hypertrophy.

Comparative microRNA profiling in relation to urinary albumin excretion in newly diagnosed hypertensive patients.

Microalbuminuria is an established early marker of endothelial dysfunction and damage. MicroRNAs (miRNAs) are emerging as essential modulators of cardiovascular physiology and disease. In the present study, we sought an association between the differential expression of related miRNAs in the peripheral blood mononuclear cells of untreated patients with newly diagnosed essential hypertension and the levels of urinary albumin excretion. We assessed the expression of the miRNAs miRNA-1, miRNA-133a, miRNA-26b, miRNA-208b, miRNA-499 and miRNA-21 in consecutive subjects with untreated newly diagnosed essential hypertension (aged 62.5±9.7 years) and with no indications of other organic heart disease. MiRNA expression levels in peripheral blood mononuclear cells were quantified by real-time reverse transcription-polymerase chain reaction. The prevalence of microalbuminuria was 9.8%. miRNA-208b and miRNA-133a were independently correlated with 24-h urinary albumin excretion. More specifically, a strong association was found between the gene expression levels of miRNA-208b in our patients' peripheral blood cells and urinary albumin (r=0.72, P<0.001). A similar association was found for miRNA-133a (r=0.372, P<0.001). In conclusion, miRNA-208b and miRNA-133a show distinct profiling in peripheral blood cells isolated from untreated patients with recently diagnosed essential hypertension. Their gene expression levels reveal a strong correlation with urinary albumin excretion levels. Our findings provide new perspectives on the development of a new generation of biomarkers for the better monitoring of end-organ damage in hypertension.

Differential expression of vascular smooth muscle-modulating microRNAs in human peripheral blood mononuclear cells: novel targets in essential hypertension.

Vascular smooth muscle cell (VSMC) phenotypic plasticity has a critical role in the pathophysiology of arterial remodeling in essential hypertension. MicroRNAs are emerging as potential biomarkers and therapeutic targets in cardiovascular disease. We assessed the expression levels of the microRNAs miR-143, miR-145, miR-21, miR-133 and miR-1, which are implicated in VSMC phenotypic modulation, in 60 patients with essential hypertension and 29 healthy individuals. All patients underwent 24-h ambulatory blood pressure (BP) monitoring. MicroRNA levels in peripheral blood mononuclear cells were quantified by real-time reverse transcription polymerase chain reaction. Hypertensive patients showed lower miR-143 (2.20±0.25 versus 4.19±0.57, P<0.001), miR-145 (13.51±1.73 versus 22.38±3.31, P=0.010) and miR-133 (8.15±1.32 versus 37.03±8.18, P<0.001) and higher miR-21 (3.08±0.32 versus 2.06±0.31, P=0.048) and miR-1 (33.94±5.19 versus 12.35±2.13 P=0.006) expression levels compared with controls. In hypertensive patients, we observed correlations of miR-143 (r = -0.380, P=0.003), miR-145 (r=-0.405, P=0.001), miR-21 (r=-0.486, P<0.001) and miR-133 (r=0.479, P<0.001) expression levels with 24-h diastolic BP. Furthermore, we observed correlations of miR-21 (r=-0.291, P=0.024), miR-1 (r=-0.312, P=0.015) and miR-133 (r=0.310, P=0.016) levels with the dipping status. Associations of miR-143 (r=-0.292, P=0.025), miR-145 (r=-0.399, P=0.002), miR-21 (r=-0.343, P=0.008) and miR-133 (r=0.370, P=0.004) levels with 24-h mean pulse pressure were also found. Our data provide important evidence that VSMC-modulating microRNAs are closely related to essential hypertension in humans and they may represent potential therapeutic targets in essential hypertension.

Arterial stiffness in hypertensives in relation to expression of angiopoietin-1 and 2 genes in peripheral monocytes.

Angiopoietins (Angs) are important angiogenic and endothelial cell growth factors with many functions, including influence on the vascular wall. Pulse-wave velocity (pwv) is an independent marker of cardiovascular adverse outcome in hypertensives, although all the pathophysiological mechanisms that affect it have not yet been determined. We investigated the relationship between arterial stiffness and Ang-1 and Ang-2 gene expression in the peripheral blood monocytes of hypertensive patients. We studied 53 patients who had untreated grade-1 or grade-2 essential hypertension and no indications of other organic heart disease. Carotid-femoral (c-f) and carotid-radial (c-r) artery waveforms were measured and pwv was determined. The monocytes were isolated using anti-CD14(+) antibodies and mRNAs were estimated by real-time quantitative reverse transcription-PCR. Ang-1 gene expression was strongly correlated with both c-f-pwv (r=0.952, P<0.001) and c-r-pwv (r=0.898, P<0.001). Similarly, Ang-2 gene expression was significantly correlated with both c-f-pwv (r=0.471, P=0.002) and c-r-pwv (r=0.437, P=0.003). Our data provide important evidence that Ang-1 and Ang-2 gene expression levels in peripheral monocytes are closely related with pwv in patients with essential hypertension. This positive correlation may suggest a link between angiogenesis and arterial stiffness in those patients.