HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Long-term spironolactone treatment reduces coronary TRPC expression, vasoconstriction, and atherosclerosis in metabolic syndrome pigs.

Abstract
Coronary transient receptor potential canonical (TRPC) channel expression is elevated in metabolic syndrome (MetS). However, differential contribution of TRPCs to coronary pathology in MetS is not fully elucidated. We investigated the roles of TRPC1 and TRPC6 isoforms in coronary arteries of MetS pigs and determined whether long-term treatment with a mineralocorticoid receptor inhibitor, spironolactone, attenuates coronary TRPC expression and associated dysfunctions. MetS coronary arteries exhibited significant atherosclerosis, endothelial dysfunction, and increased histamine-induced contractions. Immunohistochemical studies revealed that TRPC6 immunostaining was significantly greater in the medial layer of MetS pig coronary arteries compared to that in Lean pigs, whereas little TRPC6 immunostaining was found in atheromas. Conversely, TRPC1 immunostaining was weak in the medial layer but strong in MetS atheromas, where it was predominantly localized to macrophages. Spironolactone treatment significantly decreased coronary TRPC expression and dysfunctions in MetS pigs. In vivo targeted delivery of the dominant-negative (DN)-TRPC6 cDNA to the coronary wall reduced histamine-induced calcium transients in the MetS coronary artery medial layer, implying a role for TRPC6 in mediating calcium influx in MetS coronary smooth muscles. Monocyte adhesion was increased in Lean pig coronary arteries cultured in the presence of aldosterone; and spironolactone antagonized this effect, suggesting that coronary mineralocorticoid receptor activation may regulate macrophage infiltration. TRPC1 expression in atheroma macrophages was associated with advanced atherosclerosis, whereas medial TRPC6 upregulation correlated with increased histamine-induced calcium transients and coronary contractility. We propose that long-term spironolactone treatment may be a therapeutic strategy to decrease TRPC expression and coronary pathology associated with MetS.
AuthorsWennan Li, Xingjuan Chen, Ashley M Riley, S Christopher Hiett, Constance J Temm, Eleni Beli, Xin Long, Saikat Chakraborty, Mouhamad Alloosh, Fletcher A White, Maria B Grant, Michael Sturek, Alexander G Obukhov
JournalBasic research in cardiology (Basic Res Cardiol) Vol. 112 Issue 5 Pg. 54 (09 2017) ISSN: 1435-1803 [Electronic] Germany
PMID28756533 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Mineralocorticoid Receptor Antagonists
  • TRPC Cation Channels
  • TRPC6 Cation Channel
  • transient receptor potential cation channel, subfamily C, member 1
  • Spironolactone
Topics
  • Animals
  • Calcium Signaling (drug effects)
  • Cells, Cultured
  • Coronary Artery Disease (genetics, metabolism, physiopathology, prevention & control)
  • Coronary Vessels (drug effects, metabolism, physiopathology)
  • Disease Models, Animal
  • Down-Regulation
  • Drug Administration Schedule
  • Endothelium, Vascular (drug effects, metabolism, physiopathology)
  • Macrophages (drug effects, metabolism)
  • Metabolic Syndrome (drug therapy, genetics, metabolism, physiopathology)
  • Mineralocorticoid Receptor Antagonists (administration & dosage)
  • Muscle, Smooth, Vascular (drug effects, metabolism, physiopathology)
  • Spironolactone (administration & dosage)
  • Swine
  • Swine, Miniature
  • TRPC Cation Channels (drug effects, metabolism)
  • TRPC6 Cation Channel (drug effects, genetics, metabolism)
  • Time Factors
  • Tissue Culture Techniques
  • Vasoconstriction (drug effects)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: