Exercise training prevents the microvascular rarefaction in hypertension balancing angiogenic and apoptotic factors: role of microRNAs-16, -21, and -126.
Aerobic exercise training (ET) lowers hypertension and improves patient outcomes in cardiovascular disease. The mechanisms of these effects are largely unknown. We hypothesized that ET modulates microRNAs (miRNAs) involved in vascularization. miRNA-16 regulates the expression of vascular endothelial growth factor and antiapoptotic protein Bcl-2. miRNA-21 targets Bcl-2. miRNA-126 functions by repressing regulators of the vascular endothelial growth factor pathway. We investigated whether miRNA-16, -21 and -126 are modulated in hypertension and by ET. Twelve-week-old male spontaneously hypertensive rats (SHRs; n=14) and Wistar Kyoto (WKY; n=14) rats were assigned to 4 groups: SHRs, trained SHRs (SHR-T), Wistar Kyoto rats, and trained Wistar Kyoto rats. ET consisted of 10 weeks of swimming. ET reduced blood pressure and heart rate in SHR-Ts. ET repaired the slow-to-fast fiber type transition in soleus muscle and the capillary rarefaction in SHR-Ts. Soleus miRNA-16 and -21 levels increased in SHRs paralleled with a decrease of 48% and 25% in vascular endothelial growth factor and Bcl-2 protein levels, respectively. Hypertension increased Bad and decreased Bcl-x and endothelial NO synthase levels and lowered p-Bad(ser112):Bad ratio. ET in SHR-Ts reduced miRNA-16 and -21 levels and elevated vascular endothelial growth factor and Bcl-2 levels. ET restored soleus endothelial NO synthase levels plus proapoptotic and antiapoptotic mediators in SHR-Ts, indicating that the balance between angiogenic and apoptotic factors may prevent microvascular abnormalities in hypertension. miRNA-126 levels were reduced in SHRs with an increase of 51% in phosphoinositol-3 kinase regulatory subunit 2 expression but normalized in SHR-Ts. Our data show that ET promoted peripheral revascularization in hypertension, which could be associated with regulation of select miRNAs, suggesting a mechanism for its potential therapeutic application in vascular diseases.
School of Physical Education and Sport, University of Sao Paulo, Laboratory of Biochemistry and Molecular Biology of the Exercise, Av Professor Mello Moraes, 65 Cidade Universitária, São Paulo SP, 05508-900 Brazil.
Tiago
T
Fernandes
Flávio C
FC
Magalhães
Fernanda R
FR
Roque
M Ian
MI
Phillips
Edilamar M
EM
Oliveira
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001794:Blood Pressure / Q000502:physiology; D004195:Disease Models, Animal; D006339:Heart Rate / Q000502:physiology; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D055806:Microvessels / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010805:Physical Conditioning, Animal / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C571458:MIRN126 microRNA, rat; C547573:MIRN16 microRNA, rat; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D042461:Vascular Endothelial Growth Factor A; C546082:mirn21 microRNA, rat