title: Regulation of dynein-mediated autophagosomes trafficking by ASM in CASMCs.
abstract: Acid sphingomyelinase (ASM; gene symbol Smpd1) has been shown to play a crucial role in autophagy maturation by controlling lysosomal fusion with autophagosomes in coronary arterial smooth muscle cells (CASMCs). However, the underlying molecular mechanism by which ASM controls autophagolysosomal fusion remains unknown. In primary cultured CASMCs, lysosomal Ca2+ induced by 7-ketocholesterol (7-Ket, an atherogenic stimulus and autophagy inducer) was markedly attenuated by ASM deficiency or TRPML1 gene silencing suggesting that ASM signaling is required for TRPML1 channel activity and subsequent lysosomal Ca(2+) release. In these CASMCs, ASM deficiency or TRPML1 gene silencing markedly inhibited 7-Ket-induced dynein activation. In addition, 7-Ket-induced autophagosome trafficking, an event associated with lysosomal Ca(2+) release and dynein activity, was significantly inhibited in ASM-deficient (Smpd1(-/-)) CASMCs compared to that in Smpd1(+/+) CASMCs. Finally, overexpression of TRPML1 proteins restored 7-Ket-induced lysosomal Ca(2+) release and autophagosome trafficking in Smpd1-/- CASMCs. Collectively, these results suggest that ASM plays a critical role in regulating lysosomal TRPML1-Ca(2+) signaling and subsequent dynein-mediated autophagosome trafficking, which leads its role in controlling autophagy maturation in CASMCs under atherogenic stimulation.
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.|Laboratory of Chinese Herbal Pharmacy, Renmin Hospital, Hubei University of Medicine, Shiyan, China, 442000.
authors.forename: Qiufang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Pin-Lan
authors.initials: PL
authors.lastname: Li
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204.
authors.forename: Thaison
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.|Laboratory of Chinese Herbal Pharmacy, Renmin Hospital, Hubei University of Medicine, Shiyan, China, 442000.|Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002478:Cells, Cultured; D004398:Dyneins / Q000502:physiology*; D051379:Mice; D008856:Microscopy, Fluorescence; D010588:Phagosomes / Q000502:physiology*; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics
chemical_list: C577975:ASMase, mouse; D013108:Sphingomyelin Phosphodiesterase; D004398:Dyneins