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

Wennan Li, Xingjuan Chen, Ashley M. Riley, S. Christopher Hiett, Constance J. Temm, Eleni Beli, Xin Long, Saikat Chakraborty, Mouhamad Alloosh, Fletcher White, Maria B. Grant, Michael Sturek, Alexander Obukhov

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Article number54
JournalBasic Research in Cardiology
Volume112
Issue number5
DOIs
StatePublished - Sep 1 2017

Fingerprint

Spironolactone
Vasoconstriction
Atherosclerosis
Swine
Coronary Vessels
Atherosclerotic Plaques
Histamine
Therapeutics
Mineralocorticoid Receptors
Macrophages
Calcium
Pathology
Transient Receptor Potential Channels
Aldosterone
Smooth Muscle
Monocytes
Protein Isoforms
Up-Regulation
Complementary DNA

Keywords

  • Atherosclerosis
  • Coronary artery
  • Metabolic syndrome
  • Spironolactone
  • TRPC

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Long-term spironolactone treatment reduces coronary TRPC expression, vasoconstriction, and atherosclerosis in metabolic syndrome pigs. / Li, Wennan; Chen, Xingjuan; Riley, Ashley M.; Hiett, S. Christopher; Temm, Constance J.; Beli, Eleni; Long, Xin; Chakraborty, Saikat; Alloosh, Mouhamad; White, Fletcher; Grant, Maria B.; Sturek, Michael; Obukhov, Alexander.

In: Basic Research in Cardiology, Vol. 112, No. 5, 54, 01.09.2017.

Research output: Contribution to journalArticle

Li, Wennan ; Chen, Xingjuan ; Riley, Ashley M. ; Hiett, S. Christopher ; Temm, Constance J. ; Beli, Eleni ; Long, Xin ; Chakraborty, Saikat ; Alloosh, Mouhamad ; White, Fletcher ; Grant, Maria B. ; Sturek, Michael ; Obukhov, Alexander. / Long-term spironolactone treatment reduces coronary TRPC expression, vasoconstriction, and atherosclerosis in metabolic syndrome pigs. In: Basic Research in Cardiology. 2017 ; Vol. 112, No. 5.
@article{0fefd2c0f4eb40a499d619f5878ed5e7,
title = "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.",
keywords = "Atherosclerosis, Coronary artery, Metabolic syndrome, Spironolactone, TRPC",
author = "Wennan Li and Xingjuan Chen and Riley, {Ashley M.} and Hiett, {S. Christopher} and Temm, {Constance J.} and Eleni Beli and Xin Long and Saikat Chakraborty and Mouhamad Alloosh and Fletcher White and Grant, {Maria B.} and Michael Sturek and Alexander Obukhov",
year = "2017",
month = "9",
day = "1",
doi = "10.1007/s00395-017-0643-0",
language = "English (US)",
volume = "112",
journal = "Basic Research in Cardiology",
issn = "0300-8428",
publisher = "D. Steinkopff-Verlag",
number = "5",

}

TY - JOUR

T1 - Long-term spironolactone treatment reduces coronary TRPC expression, vasoconstriction, and atherosclerosis in metabolic syndrome pigs

AU - Li, Wennan

AU - Chen, Xingjuan

AU - Riley, Ashley M.

AU - Hiett, S. Christopher

AU - Temm, Constance J.

AU - Beli, Eleni

AU - Long, Xin

AU - Chakraborty, Saikat

AU - Alloosh, Mouhamad

AU - White, Fletcher

AU - Grant, Maria B.

AU - Sturek, Michael

AU - Obukhov, Alexander

PY - 2017/9/1

Y1 - 2017/9/1

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - Coronary artery

KW - Metabolic syndrome

KW - Spironolactone

KW - TRPC

UR - http://www.scopus.com/inward/record.url?scp=85026828971&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85026828971&partnerID=8YFLogxK

U2 - 10.1007/s00395-017-0643-0

DO - 10.1007/s00395-017-0643-0

M3 - Article

VL - 112

JO - Basic Research in Cardiology

JF - Basic Research in Cardiology

SN - 0300-8428

IS - 5

M1 - 54

ER -