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Physical Exercise and MicroRNAs: Molecular Mechanisms in Hypertension and Myocardial Infarction

Keywords
MicroRNAs/genetic; Hypertension; Myocardial Infarction; Exercise; Physical Exertion

Introduction

Scientific evidence shows that the regular practice of physical exercise (PE) is beneficial for various organs and systems of the human body, mainly for the heart and cardiovascular system.11 Garber CE, Blissmer B, Deschenes MR, Franklin BA, Lamonte MJ, Lee IM, et al. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: Guidance for prescribing exercise. Med Sci Sports Exerc. 2011; 43(7):1334–59. doi: 10.1249/MSS.0b013e318213fefb
https://doi.org/10.1249/MSS.0b013e318213...
In both systems, aerobic and strength PE promote physiological cardiac hypertrophy, respectively eccentric and concentric, improving myocardial function.22 Fernandes T, Soci UPR, Oliveira EM. Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants. Brazilian J Med Biol Res = Rev Bras Pesqui medicas e Biol. 2011;44(9):836–47. doi: 10.1590/s0100-879x2011007500112
https://doi.org/10.1590/s0100-879x201100...

In addition to the benefits for the heart, PE impacts blood vessels through shear stress and alters long-term vascular function, improving endothelial cell and smooth muscle cell function, generating arterial remodeling and a potential antiatherogenic effect.33 Newcomer SC, Thijssen DHJ, Green DJ. Effects of exercise on endothelium and endothelium/smooth muscle cross talk: Role of exercise-induced hemodynamics. J Appl Physiol. 2011;111(1):311-20. doi: 10.1152/japplphysiol.00033.2011
https://doi.org/10.1152/japplphysiol.000...
These benefits on the cardiovascular system occur in both healthy individuals and individuals with cardiovascular diseases, such as systemic arterial hypertension (SAH)44 Caria ACI, Nonaka CKV, Pereira CS, Soares MBP, Macambira SG, Souza BS de F. Exercise training-induced changes in microRNAs: Beneficial regulatory effects in hypertension, type 2 diabetes, and obesity. Int J Mol Sci. 2018;19(11):1–36. doi: 10.3390/ijms19113608
https://doi.org/10.3390/ijms19113608...
and myocardial infarction (MI),55 Peixoto TCA, Begot I, Bolzan DW, Machado L, Reis MS, Papa V, et al. Early Exercise-Based Rehabilitation Improves Health-Related Quality of Life and Functional Capacity After Acute Myocardial Infarction: A Randomized Controlled Trial. Can J Cardiol. 2015;31(3):308–13. doi: 10.1016/j.cjca.2014.11.014
https://doi.org/10.1016/j.cjca.2014.11.0...
for example.

However, the molecular mechanisms that govern these PE-induced benefits have not been completely elucidated, especially the mechanisms regulated by microRNAs (miRs), which are small non-coding RNAs that modulate the pattern of gene and protein expression in healthy individuals and those with cardiovascular diseases.66 Baek D, Villén J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature. 2008;455(7209):64–71. doi: 10.1038/nature07242
https://doi.org/10.1038/nature07242...

Thus, the present study aims to emphasize the importance of PE in the prevention and treatment of SAH and MI, as well as explaining the role of PE-induced miRs in these pathological conditions.

Systemic arterial hypertension, miRs and PE

SAH is a multifactorial disease and is associated with genetic factors and modifiable risk factors, such as a high-salt and high-calorie diet, smoking, stress, sedentary behavior and physical inactivity, being considered an independent risk factor for MI.77 Malachias M, Plavnik FL, Machado CA, Malta D, Scala LCN, Fuchs S. VII Brazilian Guideline of Arterial Hypertension: Chapter 1 - Concept, Epidemiology and Primary Prevention. Arq Bras Cardiol. 2016;107(3 Suppl 3):1–6. doi: 10.5935/abc.20160151.
https://doi.org/10.5935/abc.20160151...
PE in turn, is extremely beneficial for individuals with SAH because it reduces pressure levels after training.88 MacDonald JR. Potential causes, mechanisms, and implications of post exercise hypotension. J Hum Hypertens. 2002;16(4):225-36. This decrease in blood pressure is due in part to arterial remodeling, attenuating peripheral vascular resistance and also due to reduced sympathetic nerve activity.88 MacDonald JR. Potential causes, mechanisms, and implications of post exercise hypotension. J Hum Hypertens. 2002;16(4):225-36. However, the role of miRs in reducing blood pressure remains unclear.

Few studies have demonstrated the regulatory role of miRs to reduce blood pressure. In one study, the authors showed that aerobic PE lowered blood pressure in hypertensive rats by reducing the expression of miR-16 that targets the vascular endothelial growth factor (VEGF) gene, with a consequent increase in VEGF expression, improving endothelial function and decrease in miR-21 expression, with a consequent increase in its target, the Bcl-2, attenuating apoptosis, demonstrating that PE promoted an alteration in angiogenic and apoptotic factors, minimizing microvascular abnormalities, and generating peripheral revascularization in SAH.99 Fernandes T, Magalhães FC, Roque FR, Phillips MI, Oliveira EM. Exercise training prevents the microvascular rarefaction in hypertension balancing angiogenic and apoptotic factors: role of microRNAs-16, -21, and -126. Hypertens. 2012;59(2):513–20. doi: 10.1161/HYPERTENSIONAHA.111.185801
https://doi.org/10.1161/HYPERTENSIONAHA....

In this context, it was also shown that aerobic PE increased the expression of miR-27a, decreasing the expression of its target, the ACE gene, increased the expression of miR-155 reducing the expression of the AT1R and decreased the expression of miR-153, increasing the expression of ACE2. These molecular changes induced by PE, generated changes in the phenotype of the aorta artery in hypertensive rats, such as reduced aortic weight and length, decreased wall thickness, attenuation of elastin and hydroxyproline expression, with consequent improvement in the relaxation of the aorta and endothelial function, decreasing blood pressure.1010 Gu Q, Wang B, Zhang XF, Ma YP, Liu JD, Wang XZ. Contribution of renin-angiotensin system to exercise-induced attenuation of aortic remodeling and improvement of endothelial function in spontaneously hypertensive rats. Cardiovasc Pathol. 2014;23(5):298–305. doi: 10.1016/j.carpath.2014.05.006
https://doi.org/10.1016/j.carpath.2014.0...

In another study, aerobic PE increased the expression of miR-145 with modulation of the AKT signaling pathway, inducing the phenotype change of vascular smooth muscle cells in hypertensive rats, decreasing the medial layer thickness, promoting arterial remodeling and decreasing systolic and diastolic blood pressure.1111 Liao J, Zhang Y, Wu Y, Zeng F, Shi L. Akt modulation by miR-145 during exercise-induced VSMC phenotypic switching in hypertension. Life Sci. 2018;199:71–9. doi: 10.1016/j.lfs.2018.03.011
https://doi.org/10.1016/j.lfs.2018.03.01...

Corroborating the abovementioned studies, another study also showed that PE reduced systolic blood pressure in hypertensive rats, but an increase in miR-214 expression was observed in this study, exacerbating the availability of intracellular calcium and the relaxation of isolated cardiomyocytes.1212 Rodrigues JA, Prímola-Gomes TN, Soares LL, Leal TF, Nóbrega C, Pedrosa DL, et al. Physical exercise and regulation of intracellular calcium in cardiomyocytes of hypertensive rats. Arq Bras Cardiol. 2018;111(2):172–9. doi: 10.5935/abc.20180113
https://doi.org/10.5935/abc.20180113...

Thus, PE is an excellent tool to modulate the expression of miRs and regulate signaling pathways, inducing long-term cardiac and vascular phenotypic changes in hypertensive rats; however, these experiments still need to be performed in human beings with SAH, to ascertain whether these effects observed in in vivo studies occur in humans.

Myocardial infarction, miRs and PE

MI is a condition in which blood flow is reduced in one or more coronary arteries, resulting in a reduction in the supply of oxygen and nutrients to some cardiomyocytes, with consequent death of these cells. MI is considered one of the main causes of morbidity and mortality worldwide.1313 Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Vol. 116, Circulation. 2007.116(22):2634-53. doi: 10.1161/CIRCULATIONAHA.107
https://doi.org/10.1161/CIRCULATIONAHA.1...
On the other hand, regular PE practice is important to prevent and treat the individuals after an MI, but the molecular mechanisms of these benefits need to be further elucidated.

Regarding the effects of PE on the expression of miRs in post-MI in animal models, aerobic PE increased the expression of miR-29a, miR-29b and miR-29c, decreasing the expression of COL1A1 and COL3A1 genes, reducing the collagen content in the myocardium of post-MI rats quantified by the concentration of hydroxyproline, promoting improvement in cardiac function assessed by echocardiography.1414 Melo SFS, Fernandes T, Baraúna VG, Matos KC, Santos AAS, Tucci PJF, et al. Expression of microRNA-29 and collagen in cardiac muscle after swimming training in myocardial-infarcted rats. Cell Physiol Biochem. 2014;33(3):657–69. doi: 10.1159/000358642
https://doi.org/10.1159/000358642...

Another study also showed that aerobic PE exacerbated the expression of miR-29a, inhibiting the expression of TGF-β, inactivating its signaling pathway, which is pro-fibrotic. In addition to miR-29a, the authors also showed that PE increased the expression of miR-101a, which targets the FOS gene, decreasing its expression and further attenuating the TGF-β pathway. These PE-induced molecular changes resulted in reduced myocardial interstitial fibrosis in rats after MI1515 Xiao L, He H, Ma L, Da M, Cheng S, Duan Y, et al. Effects of miR-29a and miR-101a Expression on Myocardial Interstitial Collagen Generation After Aerobic Exercise in Myocardial-infarcted Rats. Arch Med Res. 2017;48(1):27–34. doi: 10.1016/j.arcmed.2017.01.006
https://doi.org/10.1016/j.arcmed.2017.01...
(Figure 1).

Figure 1
PE modulating miRs and targets in SAH and MI.

Therefore, PE has a great potential to reduce the cardiac fibrotic profile in post-MI rats through the modulation of miRs; however, these outcomes also need to be elucidated in humans, both at the molecular and tissue level.

Conclusions

Finally, PE is an excellent strategy to prevent and treat individuals with SAH and post-MI. PE-modulated miRs have been described as regulators of signaling pathways inducing modification of the cardiac and vascular phenotype in hypertensive rats, promoting blood pressure reduction, physiological cardiac hypertrophy and arterial remodeling, with improved endothelial function. Furthermore, PE-modulated miRs also regulated signaling pathways associated with the cardiac fibrosis process in post-MI rats, improving cardiac function. However, these beneficial effects of PE-regulated miRs have been described in animal models, requiring clinical trials to confirm these results obtained in vivo, being a promising and challenging new line of research.

  • Sources of Funding
    This study was partially funded by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
  • Study Association
    This study is not associated with any thesis or dissertation work.
  • Ethics approval and consent to participate
    This article does not contain any studies with human participants or animals performed by any of the authors.

Acknowledgements

This study was funded in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brazil (CAPES) - Funding Code 001.

Referências

  • 1
    Garber CE, Blissmer B, Deschenes MR, Franklin BA, Lamonte MJ, Lee IM, et al. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: Guidance for prescribing exercise. Med Sci Sports Exerc. 2011; 43(7):1334–59. doi: 10.1249/MSS.0b013e318213fefb
    » https://doi.org/10.1249/MSS.0b013e318213fefb
  • 2
    Fernandes T, Soci UPR, Oliveira EM. Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants. Brazilian J Med Biol Res = Rev Bras Pesqui medicas e Biol. 2011;44(9):836–47. doi: 10.1590/s0100-879x2011007500112
    » https://doi.org/10.1590/s0100-879x2011007500112
  • 3
    Newcomer SC, Thijssen DHJ, Green DJ. Effects of exercise on endothelium and endothelium/smooth muscle cross talk: Role of exercise-induced hemodynamics. J Appl Physiol. 2011;111(1):311-20. doi: 10.1152/japplphysiol.00033.2011
    » https://doi.org/10.1152/japplphysiol.00033.2011
  • 4
    Caria ACI, Nonaka CKV, Pereira CS, Soares MBP, Macambira SG, Souza BS de F. Exercise training-induced changes in microRNAs: Beneficial regulatory effects in hypertension, type 2 diabetes, and obesity. Int J Mol Sci. 2018;19(11):1–36. doi: 10.3390/ijms19113608
    » https://doi.org/10.3390/ijms19113608
  • 5
    Peixoto TCA, Begot I, Bolzan DW, Machado L, Reis MS, Papa V, et al. Early Exercise-Based Rehabilitation Improves Health-Related Quality of Life and Functional Capacity After Acute Myocardial Infarction: A Randomized Controlled Trial. Can J Cardiol. 2015;31(3):308–13. doi: 10.1016/j.cjca.2014.11.014
    » https://doi.org/10.1016/j.cjca.2014.11.014
  • 6
    Baek D, Villén J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature. 2008;455(7209):64–71. doi: 10.1038/nature07242
    » https://doi.org/10.1038/nature07242
  • 7
    Malachias M, Plavnik FL, Machado CA, Malta D, Scala LCN, Fuchs S. VII Brazilian Guideline of Arterial Hypertension: Chapter 1 - Concept, Epidemiology and Primary Prevention. Arq Bras Cardiol. 2016;107(3 Suppl 3):1–6. doi: 10.5935/abc.20160151.
    » https://doi.org/10.5935/abc.20160151
  • 8
    MacDonald JR. Potential causes, mechanisms, and implications of post exercise hypotension. J Hum Hypertens. 2002;16(4):225-36.
  • 9
    Fernandes T, Magalhães FC, Roque FR, Phillips MI, Oliveira EM. Exercise training prevents the microvascular rarefaction in hypertension balancing angiogenic and apoptotic factors: role of microRNAs-16, -21, and -126. Hypertens. 2012;59(2):513–20. doi: 10.1161/HYPERTENSIONAHA.111.185801
    » https://doi.org/10.1161/HYPERTENSIONAHA.111.185801
  • 10
    Gu Q, Wang B, Zhang XF, Ma YP, Liu JD, Wang XZ. Contribution of renin-angiotensin system to exercise-induced attenuation of aortic remodeling and improvement of endothelial function in spontaneously hypertensive rats. Cardiovasc Pathol. 2014;23(5):298–305. doi: 10.1016/j.carpath.2014.05.006
    » https://doi.org/10.1016/j.carpath.2014.05.006
  • 11
    Liao J, Zhang Y, Wu Y, Zeng F, Shi L. Akt modulation by miR-145 during exercise-induced VSMC phenotypic switching in hypertension. Life Sci. 2018;199:71–9. doi: 10.1016/j.lfs.2018.03.011
    » https://doi.org/10.1016/j.lfs.2018.03.011
  • 12
    Rodrigues JA, Prímola-Gomes TN, Soares LL, Leal TF, Nóbrega C, Pedrosa DL, et al. Physical exercise and regulation of intracellular calcium in cardiomyocytes of hypertensive rats. Arq Bras Cardiol. 2018;111(2):172–9. doi: 10.5935/abc.20180113
    » https://doi.org/10.5935/abc.20180113
  • 13
    Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Vol. 116, Circulation. 2007.116(22):2634-53. doi: 10.1161/CIRCULATIONAHA.107
    » https://doi.org/10.1161/CIRCULATIONAHA.107
  • 14
    Melo SFS, Fernandes T, Baraúna VG, Matos KC, Santos AAS, Tucci PJF, et al. Expression of microRNA-29 and collagen in cardiac muscle after swimming training in myocardial-infarcted rats. Cell Physiol Biochem. 2014;33(3):657–69. doi: 10.1159/000358642
    » https://doi.org/10.1159/000358642
  • 15
    Xiao L, He H, Ma L, Da M, Cheng S, Duan Y, et al. Effects of miR-29a and miR-101a Expression on Myocardial Interstitial Collagen Generation After Aerobic Exercise in Myocardial-infarcted Rats. Arch Med Res. 2017;48(1):27–34. doi: 10.1016/j.arcmed.2017.01.006
    » https://doi.org/10.1016/j.arcmed.2017.01.006

Publication Dates

  • Publication in this collection
    10 June 2022
  • Date of issue
    2022

History

  • Received
    17 June 2021
  • Reviewed
    21 Oct 2021
  • Accepted
    08 Dec 2021
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