BKCa compensates impaired coronary vasoreactivity through RhoA/ROCK pathway in hind-limb unweighted rats

FASEB J. 2019 Dec;33(12):13358-13366. doi: 10.1096/fj.201901273R. Epub 2019 Sep 17.

Abstract

Previous studies have demonstrated cardiac and vascular remodeling induced by microgravity exposure. Yet, as the most important branch of vasculatures circulating the heart, the coronary artery has been seldomly studied about its adaptations under microgravity conditions. Large-conductance Ca2+-activated potassium channel (BKCa) and the Ras homolog family member A (RhoA)/Rho kinase (ROCK) pathway play key roles in control of vascular tone and mediation of microgravity-induced vascular adjustments. Therefore, we investigated the adaptation of coronary vasoreactivity to simulated microgravity and the role of BKCa and the RhoA/ROCK pathway in it. Four-week-old hind-limb unweighted (HU) rats were adopted to simulate effects of microgravity. Right coronary artery (RCA) constriction was measured by isometric force recording. The activity and expression of BKCa and the RhoA/ROCK pathway were examined by Western blot, patch-clamp recordings, and immunoprecipitation. We found HU significantly decreased RCA vasoconstriction to KCl, serotonin, and U-46619, but increased protein expression and current densities of BKCa, inhibition of which by iberiotoxin (IBTX) further decreased RCA vasoconstriction (P < 0.05). Expression of RhoA and ROCK as well as active RhoA and phosphorylation of myosin light chain (MLC) at Ser19 and MLC phosphatase target-1 at Thr696 were significantly increased by HU, and ROCK inhibitor Y-27632 exerted greater suppressing effect on HU RCA vasoconstriction than that of control (P < 0.05). BKCa opener NS1619 increased HU RCA vasoconstriction, which was blocked by both RhoA and ROCK inhibitor, similar to the effect of IBTX. These results indicate that HU impairs coronary vasoconstriction but enhances BKCa activity acting as a protective mechanism avoiding excessive decrease of coronary vasoreactivity through activation of the RhoA/ROCK pathway.-Wu, Y., Yue, Z., Wang, Q., Lv, Q., Liu, H., Bai, Y., Li, S., Xie, M., Bao, J., Ma, J., Zhu, X., Wang, Z. BKCa compensates impaired coronary vasoreactivity through RhoA/ROCK pathway in hind-limb unweighted rats.

Keywords: coronary artery; hind-limb unweighting; vasoconstriction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight
  • Calcium / metabolism
  • Coronary Vessels / drug effects
  • Coronary Vessels / physiology*
  • Hindlimb Suspension / physiology*
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / genetics
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / metabolism*
  • Male
  • Muscle, Smooth, Vascular / blood supply
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / physiology
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Vasoconstriction / drug effects
  • Vasoconstriction / physiology*
  • Weightlessness Simulation
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism*
  • rho-Associated Kinases / genetics
  • rho-Associated Kinases / metabolism*

Substances

  • Kcnma1 protein, rat
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
  • Protein Kinase Inhibitors
  • ROCK1 protein, rat
  • ROCK2 protein, rat
  • rho-Associated Kinases
  • RhoA protein, rat
  • rho GTP-Binding Proteins
  • Calcium