Original Article | Published:

Epigenetic regulation of L-type voltage-gated Ca2+ channels in mesenteric arteries of aging hypertensive rats

Hypertension Research volume 40, pages 441449 (2017) | Download Citation

Abstract

Accumulating evidence has shown that epigenetic regulation is involved in hypertension and aging. L-type voltage-gated Ca2+ channels (LTCCs), the dominant channels in vascular myocytes, greatly contribute to arteriole contraction and blood pressure (BP) control. We investigated the dynamic changes and epigenetic regulation of LTCC in the mesenteric arteries of aging hypertensive rats. LTCC function was evaluated by using microvascular rings and whole-cell patch-clamp in the mesenteric arteries of male Wistar-Kyoto rats and spontaneously hypertensive rats at established hypertension (3 month old) and an aging stage (16 month old), respectively. The expression of the LTCC α1C subunit was determined in the rat mesenteric microcirculation. The expression of miR-328, which targets α1C mRNA, and the DNA methylation status at the promoter region of the α1C gene (CACNA1C) were also determined. In vitro experiments were performed to assess α1C expression after transfection of the miR-328 mimic into cultured vascular smooth muscle cells (VSMCs). The results showed that hypertension superimposed with aging aggravated BP and vascular remodeling. Both LTCC function and expression were significantly increased in hypertensive arteries and downregulated with aging. miR-328 expression was inhibited in hypertension, but increased with aging. There was no significant difference in the mean DNA methylation of CACNA1C among groups, whereas methylation was enhanced in the hypertensive group at specific sites on a CpG island located upstream of the gene promoter. Overexpression of miR-328 inhibited the α1C level of cultured VSMCs within 48 h. The results of the present study indicate that the dysfunction of LTCCs may exert an epigenetic influence at both pre- and post-transcriptional levels during hypertension pathogenesis and aging progression. miR-328 negatively regulated LTCC expression in both aging and hypertension.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    . Hypertension in the elderly. Annu Rev Med 1995; 46: 27–35.

  2. 2.

    . A review of the genetics of essential hypertension. Curr Opin Cardiol 2007; 22: 176–184.

  3. 3.

    , , , , , , , . Augmented vascular smooth muscle cell stiffness and adhesion when hypertension is superimposed on aging. Hypertension 2015; 65: 370–377.

  4. 4.

    . Aging, arterial stiffness, and hypertension. Hypertension 2015; 65: 252–256.

  5. 5.

    , , , . Therapeutic potential of pharmacologically targeting arteriolar myogenic tone. Trends Pharmacol Sci 2009; 30: 363–374.

  6. 6.

    , , , , , . Exercise intensity-dependent reverse and adverse remodeling of voltage-gated Ca2+ channels in mesenteric arteries from spontaneously hypertensive rats. Hypertens Res 2015; 38: 656–665.

  7. 7.

    , . Voltage-dependent Ca2+ channels in arterial smooth muscle cells. Kidney Blood Press Res 1997; 20: 355–371.

  8. 8.

    , , , . High blood pressure upregulates arterial L-type Ca2+ channels: is membrane depolarization the signal? Circ Res 2004; 94: e97–104.

  9. 9.

    , , , , . Role of epigenetics in pulmonary hypertension. Am J Physiol Cell Physiol 2014; 306: C1101–C1105.

  10. 10.

    , , , , , , . Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet 2007; 39: 457–466.

  11. 11.

    , , , , , , . Factors underlying variable DNA methylation in a human community cohort. Proc Natl Acad Sci USA 2012; 109: 17253–17260.

  12. 12.

    , , , , , , . Differential expression and DNA methylation of angiotensin type 1A receptors in vascular tissues during genetic hypertension development. Mol Cell Biochem 2015; 402: 1–8.

  13. 13.

    , , . Methyl nutrients, DNA methylation, and cardiovascular disease. Mol Nutr Food Res 2014; 58: 172–182.

  14. 14.

    , , . DNA methylation and healthy human aging. Aging Cell 2015; 14: 924–932.

  15. 15.

    , . Aging and DNA methylation. BMC Biol 2015; 13: 7–15.

  16. 16.

    , , . MicroRNA-based therapeutic approaches in the cardiovascular system. Cardiovasc Ther 2012; 30: e9–e15.

  17. 17.

    , , , , . Mechanisms and therapeutic potential of microRNAs in hypertension. Drug Discov Today 2015; 20: 1188–1204.

  18. 18.

    , . MicroRNAs in hypertension: mechanisms and therapeutic targets. Curr Hypertens Rep 2012; 14: 79–87.

  19. 19.

    , . Targeting smooth muscle microRNAs for therapeutic benefit in vascular disease. Pharmacol Res 2013; 75: 28–36.

  20. 20.

    , , . MicroRNAs in vascular aging and atherosclerosis. Ageing Res Rev 2014; 17: 68–78.

  21. 21.

    , , , , . Role, function and therapeutic potential of microRNAs in vascular aging. Curr Vasc Pharmacol 2015; 13: 324–330.

  22. 22.

    , , , , , , , , . The microRNA-328 regulates hypoxic pulmonary hypertension by targeting at insulin growth factor 1 receptor and L-type calcium channel-alpha1C. Hypertension 2012; 59: 1006–1013.

  23. 23.

    , , , , , , , , , , , , , . MicroRNA-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation 2010; 122: 2378–2387.

  24. 24.

    , , , , , , . Chronic exercise normalizes changes in Cav 1.2 and KCa 1.1 channels in mesenteric arteries from spontaneously hypertensive rats. Br J Pharmacol 2015; 172: 1846–1858.

  25. 25.

    , . Preparation of primary cultured mesenteric artery smooth muscle cells for fluorescent imaging and physiological studies. Nat Protoc 2006; 1: 2681–2687.

  26. 26.

    . Hypertension in old age. P R Health Sci J 1995; 14: 217–221.

  27. 27.

    , , , , . Upregulation of L-type Ca2+ channels in mesenteric and skeletal arteries of SHR. Hypertension 2002; 40: 214–219.

  28. 28.

    , , , , . Voltage-dependent Ca2+ channels in resistance arteries from spontaneously hypertensive rats. Circ Res 1993; 73: 1090–1099.

  29. 29.

    , , , . Disrupting calcium channel expression to lower blood pressure: new targeting of a well-known channel. Mol Interv 2006; 6: 304–310.

  30. 30.

    , , , , , . Attenuation of L-type Ca2+ channel expression and vasomotor response in the aorta with age in both Wistar-Kyoto and spontaneously hypertensive rats. PLoS ONE 2014; 9: e88975.

  31. 31.

    , , , , , , , . Effects of aging on Ca2+ signaling in murine mesenteric arterial smooth muscle cells. Mech Ageing Dev 2006; 127: 315–323.

  32. 32.

    , , , , , , , , , , . Investigation of microRNA expression in human serum during the aging process. J Gerontol A Biol Sci Med Sci 2015; 70: 102–109.

  33. 33.

    , , , , . Up-regulation of key microRNAs, and inverse down-regulation of their predicted oxidative phosphorylation target genes, during aging in mouse brain. Neurobiol Aging 2011; 32: 944–955.

  34. 34.

    , . Epigenetic control of haematopoietic stem cell aging and its clinical implications. Stem Cells Int 2016; 2016: 5797521.

  35. 35.

    , , , , , , , , , , , , . Chronic atrial fibrillation increases microRNA-21 in human atrial myocytes decreasing L-type calcium current. Circ Arrhythm Electrophysiol 2014; 7: 861–868.

  36. 36.

    , , , , , , , , , , , , , , , , , . Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy. Nat Struct Mol Biol 2011; 18: 840–845.

  37. 37.

    , . Calcium antagonists. Prog Cardiovasc Dis 2004; 47: 34–57.

  38. 38.

    , , , . Combination therapy in hypertension: a focus on angiotensin receptor blockers and calcium channel blockers. Am J Ther 2010; 17: 61–67.

Download references

Acknowledgements

This work was financially supported by grants from the National Natural Science Foundation of China (31371201); the Chinese Universities Scientific Fund (2015ZD008, 2016RC001); Research project of the General Administration of Sport of China (2015B035); and the Beijing Natural Science Foundation (to LS).

Author information

Affiliations

  1. Department of Exercise Physiology, Beijing Sport University, Beijing, China

    • Jingwen Liao
    • , Yanyan Zhang
    • , Fang Ye
    • , Lin Zhang
    • , Yu Chen
    • , Fanxing Zeng
    •  & Lijun Shi
  2. Department of Sport and Health Sciences, Guangzhou Institute of Physical Education, Guangzhou, China

    • Jingwen Liao

Authors

  1. Search for Jingwen Liao in:

  2. Search for Yanyan Zhang in:

  3. Search for Fang Ye in:

  4. Search for Lin Zhang in:

  5. Search for Yu Chen in:

  6. Search for Fanxing Zeng in:

  7. Search for Lijun Shi in:

Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Lijun Shi.

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/hr.2016.167

Further reading