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.
Highlights
Metabolic syndrome (MetS) is a condition characterized by central obesity, insulin resistance, glucose intolerance, dyslipidemia, hypertension, and atherosclerosis [23, 38, 50]
Thirty-six castrated Ossabaw miniature pigs were subdivided into three groups: Lean, metabolic syndrome (MetS), and metabolic syndrome treated with spironolactone
To investigate the effect of long-term spironolactone treatment on transient receptor potential canonical (TRPC) expression and coronary pathology in metabolic syndrome pigs, Ossabaw miniature pigs were subdivided into three groups: Lean, metabolic syndrome (MetS), and metabolic syndrome treated with spironolactone (MetS-SN)
Summary
Metabolic syndrome (MetS) is a condition characterized by central obesity, insulin resistance, glucose intolerance, dyslipidemia, hypertension, and atherosclerosis [23, 38, 50]. Atherosclerotic plaques are made of lipids, cholesterol, extracellular matrix deposits, proliferating smooth muscle cells (SMCs), T-lymphocytes, foam cells, and macrophages. These lesions decrease the vessel lumen area and cause obstruction of blood flow. Atherosclerotic coronary arteries exhibit increased spasticity [46, 49] that may lead to angina, myocardial infarction, and sudden death [27]. Angina patients present with elevated plasma histamine concentration [43], indicating that histamine-induced coronary artery contractions may contribute to some ischemic episodes in these patients. Histamine is known to contract coronary arteries, with the presence of atherosclerosis potentiating the contractile response [11, 22]. TRPC channels are implicated in the pathogenesis of hypertension and neointimal hyperplasia [1, 33, 40]
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