Nonsteroidal Anti-inflammatory Drugs Inhibit Vascular Smooth Muscle Cell Proliferation by Enabling the Ca2+-dependent Inactivation of Calcium Release-activated Calcium/Orai Channels Normally Prevented by Mitochondria

Abstract

Abnormal vascular smooth muscle cell (VSMC) proliferation contributes to occlusive and proliferative disorders of the vessel wall. Salicylate and other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit VSMC proliferation by an unknown mechanism unrelated to anti-inflammatory activity. In search for this mechanism, we have studied the effects of salicylate and other Increased vascular smooth muscle cell (VSMC) 3 proliferation, a process controlled by Ca 2ϩ channel switching, is a key event in the development of atherosclerosis, restenosis, and other occlusive and proliferative disorders of the vasculature (1, 2). Salicylate, the major aspirin metabolite, and other nonsteroidal anti-inflammatory drugs (NSAIDs) may induce direct, platelet-independent effects on the vascular wall (3-5). For example, salicylate effectively inhibits VSMC proliferation and DNA synthesis in vivo and in vitro without inducing cellular toxicity or apoptosis (4).A series of NSAIDs, including aspirin, ibuprofen, indomethacin, and sulindac, induce a dose-dependent inhibition of proliferation in A10 cells (6, 7), a VSMC cell line derived from embryonic rat aorta. The effects of NSAIDs occur in the absence of cytotoxicity and are independent of cyclooxygenase (7). Aspirin treatment also inhibits neointimal proliferation in dogs fed a cholesterol-enriched diet (8) and prevents the development of atherosclerosis in rabbits (9). Therefore, NSAIDs inhibit VSMC proliferation and show salutary effects in the treatment of vascular proliferative disorders by a yet unknown mechanism of action unrelated to anti-inflammatory activity.Intracellular Ca 2ϩ is a major trigger for vasoconstriction and a stimulus for VSMC proliferation (1, 2, 10). Several Ca 2ϩ channels participate in regulating intracellular Ca 2ϩ , including voltage-operated and store-operated Ca 2ϩ channels (10, 11). SOCE is activated after the emptying of intracellular Ca 2ϩ stores by physiological stimuli and is involved in cell proliferation in several cell types, including T cells (12,13). In these cells, SOCE requires not only the activating signal from the empty store but also the close proximity of functional mitochondria acting as Ca 2ϩ sinks to prevent the strong Ca 2ϩ -dependent inactivation of SOC channels (14 -18

STIM and Orai proteins as novel targets for cancer therapy. A Review in the Theme: Cell and Molecular Processes in Cancer Metastasis

“…For instance, NSAIDs were demonstrated to abrogate SOCE and STIM1-COX-2-mediated migration in colorectal cancer cell lines (108). Similarly, NSAIDs were also reported to block vascular smooth muscle cell proliferation by indirect inhibition of Orai1-mediated I CRAC (73). However, the efficacy of such drugs in impeding cancer growth is likely marginal and in the absence of in vivo studies the potential of NSAIDs in controlling STIM-Orai-mediated tumor development is uncertain.…”

The store-operated calcium channels in cancer metastasis from cell migration invasion to metastatic colonization

“…Non-steroidal anti-inflammatory drugs such as Aspirin have shown promising chemopreventive potential in various cancers (131). Notably, many NSAIDs, such as indomethacin, ibuprofen and sulindac, are also able to inhibit SOCE (132). Therefore, these over-the-counter pain killers could potentially be used to target SOCE and the inflammatory pathways downstream of SOCE in cancer.…”

Inflammation alters regional mitochondrial Ca2+ in human airway smooth muscle cells

“…In human ASM, mitochondria are present in large numbers (79), and, interestingly, mitochondrial biogenesis is enhanced in asthma (28). Whether such changes can contribute to altered Ca 2ϩ homeostasis or other features of asthma, such as airway remodeling, is not known.Mitochondrial Ca 2ϩ uptake during agonist stimulation has been observed in different cell types (13,25,33,38,48,55,56,65) and is thought to decrease local Ca 2ϩ gradients for sarcoplasmic reticulum (SR)/endoplasmic reticulum Ca 2ϩ refilling while maintaining or enhancing store-operated Ca 2ϩ entry (SOCE) (24,37,41,45,50,81). Some theoretical models of Ca 2ϩ signaling in smooth muscle that include mitochondria also suggest a role for modulating [Ca 2ϩ ] cyt regulatory mechanisms (66, 67).…”