PKC-dependent coupling of calcium permeation through transient receptor potential canonical 3 (TRPC3) to calcineurin signaling in HL-1 myocytes

A TRPC3 Blocker, Ethyl-1-(4-(2,3,3-Trichloroacrylamide)Phenyl)-5-(Trifluoromethyl)-1H-Pyrazole-4-Carboxylate (Pyr3), Prevents Stent-Induced Arterial Remodeling

“…A particular challenge in drug-eluting stent development is the identification of suitable antiproliferative compounds that do not suppress re-endothelialization, which is essential for the prevention of late thrombotic events after angioplasty (Finn et al, 2007). In line with profound TRPC3 expression in human arterial smooth muscle and its importance for control of transcriptional programs, as demonstrated by use of dominant negative TRPC3 pore mutations (Poteser et al, 2011), we observed inhibition of arterial proliferation by the TRPC3 inhibitor Pyr3. As the antiproliferative action of Pyr3 might be restricted to tissues with prominent TRPC3 expression, we also tested its effect in human endothelial cells, which typically display low TRPC3 expression (Paria et al, 2004) but prominent expression of TRPC1, TRPC4 and TRPC6 (Cioffi and Stevens, 2006;Zhang and Gutterman, 2011;Cioffi et al, 2012).…”

“…TRPC signaling is likely involved in early steps of pathological remodeling processes, specifically in the cardiovascular system. This pathophysiological role is substantiated by the recently identified linkage of TRPC Ca 21 signals to control gene transcription (Poteser et al, 2011). TRPC channels generate localized Ca 21 signals that govern transcription factors, such as NFAT.…”

“…On the other hand, suppression of smooth muscle proliferation in response to inhibition of TRPC3 function was also confirmed by dominant negative knock-down ( Supplementary Fig. 3) using well established TRPC3 constructs (Poteser et al, 2011).…”

“…Nonetheless, a role for TRPC3 expression in endothelial proliferation has been recently suggested from studies using siRNA knock-down strategy (Antigny et al, 2012). One explanation for the discrepant effects of siRNA knock-down and selective channel block might be the recently identified scaffold function of TRPC3 in Ca 21 transcription coupling (Poteser et al, 2011). Thus, expression of the protein (but not necessarily channel function) might be important in endothelial cells.…”

“…While TRPC4, TRPC1 and TRPC6 appear highly expressed and of functional significance in endothelial cells (Freichel et al, 2004;Paria et al, 2004;Graziani et al, 2010), TRPC6 and TRPC3 have been identified as important players in diseased states of vascular smooth muscle (Thippegowda et al, 2010;Yao and Garland, 2005;Liu et al, 2010;Park et al, 2011). As TRPC3 represents a Ca 21 entry channel that is tightly linked to transcriptional control (Poteser et al, 2011) and is expressed at substantial levels in human arterial smooth muscle, we set out to evaluate the therapeutic potential of selective inhibition of this Ca 21 entry channel. Utilizing a recently identified selective inhibitor of TRPC3 (Glasnov et al, 2009;Kiyonaka et al, 2009) and a novel in vitro model of stent-induced smooth muscle hyperplasia, we provide the first evidence for the suitability of isoform selective suppression of TRPC signaling as an effective DES strategy.…”