Introduction:
Primary hypertension (PH) is a multifactorial disease influenced by genetic, epigenetic, and environmental factors. Despite the occurrence of PH-associated cardiovascular events in youth, the molecular mechanism(s) of target organ damage (TOD) are unknown.
Objectives:
(1) To identify an epigenetic signature and gene expression profiles in adolescents with low blood pressure (BP) and normal left ventricular mass (LVM) compared to those with high BP and high LVM; and (2) to determine novel gene targets and associated signaling pathways for future investigation and intervention.
Methods and Results:
A total of 397 participants (mean age 15.6 ±1.7 years, 59% male, 63% Caucasian) were enrolled across the distribution of BP. The average daytime ambulatory systolic BP recorded in healthy and hypertensive participants was 112 ±9.71 and 133 ±7.2 mmHg (
p<0.05
) respectively. Clinical measures revealed higher body mass index (26.8 ±7.02
vs
29.6 ±7.88 Kg/m
2
;
p<0.05
), and abnormal circulatory HDL (47.4 ±12.1
vs
43.4 ±11.7 mg/dL;
p<0.05
), glucose (87.8 ±7.98
vs
90.8 ±8.17 mg/dL;
p<0.05
), insulin (17.8 ±14.3
vs
23.7 ±19 μIU/dL;
p<0.05
), creatinine (0.718 ±0.13
vs
0.727 ±0.17 mg/dL;
p<0.05
), uric acid (5.4 ±1.63
vs
6.04 ±1.52 mg/dL;
p<0.05
), CRP (1.35 ±1.8
vs
1.92 ±2.14 mg/dL;
p<0.05
), and left ventricular hypertrophy (LVM/ht
2.7
; 31.4 ±6.74
vs
33.5 ±7.15 g/m
2.7
;
p<0.05
), and arterial stiffness (Pulse wave velocity; 4.83 ±0.69
vs
5.35 ±0.92 m/sec;
p<0.05
). Using peripheral blood mononuclear cells, mRNA-Seq, miRNA-Seq, and whole-genome DNA methylation analysis revealed master genes, and regulatory pathways related to BP regulation, tissue fibrosis and cardiovascular remodeling. Our study reveals a novel PH-associated TOD mechanism, showing angiogenesis inhibition mediated by
VASH1
(Vasohibin-1) upregulation and downtrends in
VASH2
(Vasohibin-2),
VEGFC
(Vascular endothelial growth factor C),
HIF1α
(Hypoxia-inducible factor 1-alpha), and
IGF1
(Insulin Like Growth Factor 1). Moreover,
VASH1
targeting miRNA
hsa-miR-30e-5p
is inversely regulated.
Conclusion:
Angiogenesis inhibition in the presence of common demographic and clinical intermediate-phenotypes may contribute to the development of TOD in hypertensive youth.
MiR-21 and miR-133 levels in peripheral blood mononuclear cells associate with left ventricular diastolic dysfunction in patients with diastolic heart failure
