Ca2+ Entry Through Reverse Mode Na+/Ca2+ Exchanger Contributes to Store Operated Channel-Mediated Neointima Formation After Arterial Injury

Bei Liu, Bin Zhang, Shiliang Huang, Lixia Yang, Carolyn M. Roos, Michael A. Thompson, Y.s. Prakash, Jie Zang, Jordan D Miller, Ruiwei Guo

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Abstract

Background: Na+/Ca2+ exchange (NCX) reversal-mediated Ca2+ entry is a critical pathway for stimulating proliferation in many cell lines. However, the role of reverse-mode NCX1 in neointima formation and atherosclerosis remains unclear. The aims of the present study were to investigate the functional role of NCX1 in the pathogenesis of atherosclerosis and vascular smooth muscle cell (VSMC) proliferation, and to determine the interaction between NCX1 and store depletion in VSMCs. Methods: A rat balloon injury model was established to examine the effect of the knockdown of NCX1 on neointima formation after injury. VSMCs were cultured to verify that NCX1 knockdown suppressed serum-induced VSMC proliferation. Results: The results showed that balloon injury induced neointima formation and upregulated NCX1 expression at 7 and 14 days after injury in rat carotid arteries (1.18- and 1.45-fold, respectively). A lentivirus vector expressing short hairpin (sh)RNA against rat NCX1 dramatically downregulated NCX1, proliferating cell nuclear antigen (PCNA) and Ki-67 expression, and suppressed neointima formation in vivo (62% at 7 days and 70% at 14 days). KB-R7943 (an inhibitor of reverse-mode NCX1) and NCX1 knockdown significantly inhibited serum-induced VSMC proliferation (65% at 72 hours and 41% at 72 hours, respectively), determined according to PCNA and Ki-67 expression and cell counting in vitro, and markedly suppressed store depletion-mediated Ca2+ entry and peripheral cytosolic Na+ transients in VSMCs. Conclusions: Reverse-mode NCX1 is activated by store depletion and is required for proliferative VSMC proliferation and neointima formation after arterial injury.

Original languageEnglish (US)
JournalCanadian Journal of Cardiology
DOIs
StateAccepted/In press - Jan 1 2018

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ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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