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.