PMID- 38423188
OWN - NLM
STAT- MEDLINE
DCOM- 20240326
LR  - 20240326
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Linking)
VI  - 222
DP  - 2024 Apr
TI  - Ca(v)3.1 T-type calcium channel blocker NNC 55-0396 reduces atherosclerosis by 
      increasing cholesterol efflux.
PG  - 116096
LID - S0006-2952(24)00079-0 [pii]
LID - 10.1016/j.bcp.2024.116096 [doi]
AB  - Calcium channel blockers (CCBs) are commonly used as antihypertensive agents. 
      While certain L-type CCBs exhibit antiatherogenic effects, the impact of 
      Ca(v)3.1 T-type CCBs on antiatherogenesis and lipid metabolism remains 
      unexplored. NNC 55-0396 (NNC) is a highly selective blocker of T-type calcium 
      channels (Ca(v)3.1 channels). We investigated the effects of NNC on relevant 
      molecules and molecular mechanisms in human THP-1 macrophages. Cholesterol 
      efflux, an indicator of reverse cholesterol transport (RCT) efficiency, was 
      assessed using [3H]-labeled cholesterol. In vivo, high cholesterol diet (HCD)-fed 
      LDL receptor knockout (Ldlr(-/-)) mice, an atherosclerosis-prone model, underwent 
      histochemical staining to analyze plaque burden. Treatment of THP-1 macrophages 
      with NNC facilitated cholesterol efflux and reduced intracellular cholesterol 
      accumulation. Pharmacological and genetic interventions demonstrated that NNC 
      treatment or Ca(v)3.1 knockdown significantly enhanced the protein expression of 
      scavenger receptor B1 (SR-B1), ATP-binding cassette transporter A1 (ABCA1), 
      ATP-binding cassette transporter G1 (ABCG1), and liver X receptor alpha (LXRalpha) 
      transcription factor. Mechanistic analysis revealed that NNC activates p38 and 
      c-Jun N-terminal kinase (JNK) phosphorylation, leading to increased expression of 
      ABCA1, ABCG1, and LXRalpha-without involving the microRNA pathway. LXRalpha isrequired 
      for NNC-induced ABCA1 and ABCG1 expression. Administering NNC diminished 
      atherosclerotic lesion area and lipid deposition in HCD-fed Ldlr(-/-) mice. NNC's 
      anti-atherosclerotic effects, achieved through enhanced cholesterol efflux and 
      inhibition of lipid accumulation, suggest a promising therapeutic approach for 
      hypertensive patients with atherosclerosis. This research highlights the 
      potential of Ca(v)3.1 T-type CCBs in addressing cardiovascular complications 
      associated with hypertension.
CI  - Copyright (c) 2024 Elsevier Inc. All rights reserved.
FAU - Tsai, Min-Chien
AU  - Tsai MC
AD  - Department of Physiology and Biophysics, Graduate Institute of Physiology, 
      National Defense Medical Center, Taipei 11490, Taiwan.
FAU - Cho, Rou-Ling
AU  - Cho RL
AD  - Division of Cardiology, Department of Medicine, Tri-Service General Hospital, 
      National Defense Medical Center, Taipei 11490, Taiwan.
FAU - Lin, Chin-Sheng
AU  - Lin CS
AD  - Division of Cardiology, Department of Medicine, Tri-Service General Hospital, 
      National Defense Medical Center, Taipei 11490, Taiwan; Graduate Institute of Life 
      Sciences, National Defense Medical Center, Taipei 11490, Taiwan.
FAU - Jheng, Yu-Sin
AU  - Jheng YS
AD  - Department of Physiology and Biophysics, Graduate Institute of Physiology, 
      National Defense Medical Center, Taipei 11490, Taiwan.
FAU - Lien, Chih-Feng
AU  - Lien CF
AD  - Division of Cardiology, Department of Medicine, Tri-Service General Hospital, 
      National Defense Medical Center, Taipei 11490, Taiwan.
FAU - Chen, Chien-Chang
AU  - Chen CC
AD  - Taiwan International Graduate Program in Molecular Medicine, National Yang Ming 
      Chiao Tung University and Academia Sinica, Taipei 115, Taiwan; Institute of 
      Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
FAU - Tzeng, Bing-Hsiean
AU  - Tzeng BH
AD  - Division of Cardiology, Department of Medicine, Tri-Service General Hospital, 
      National Defense Medical Center, Taipei 11490, Taiwan; Cardiovascular Medical 
      Center, Far Eastern Memorial Hospital, Taipei 220, Taiwan. Electronic address: 
      894020086@mail.ndmctsgh.edu.tw.
LA  - eng
PT  - Journal Article
DEP - 20240227
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Calcium Channel Blockers)
RN  - 0A7CE46ERM (NNC 55-0396)
RN  - 0 (Liver X Receptors)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (ATP Binding Cassette Transporter 1)
RN  - 0 (Benzimidazoles)
RN  - 0 (Cyclopropanes)
RN  - 0 (Naphthalenes)
SB  - IM
MH  - Humans
MH  - Animals
MH  - Mice
MH  - Calcium Channel Blockers/pharmacology/therapeutic use
MH  - *Atherosclerosis/drug therapy/prevention & control/metabolism
MH  - Liver X Receptors/metabolism
MH  - Cholesterol/metabolism
MH  - *Hypercholesterolemia/drug therapy
MH  - ATP-Binding Cassette Transporters/metabolism
MH  - ATP Binding Cassette Transporter 1/genetics/metabolism
MH  - *Benzimidazoles
MH  - *Cyclopropanes
MH  - *Naphthalenes
OTO - NOTNLM
OT  - ABCA1
OT  - ABCG1
OT  - Atherosclerosis
OT  - Ca(v)3.1 T-type calcium channel
OT  - Cholesterol efflux
OT  - Macrophage
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2024/03/01 01:22
MHDA- 2024/03/26 06:45
CRDT- 2024/02/29 19:14
PHST- 2023/09/27 00:00 [received]
PHST- 2024/01/29 00:00 [revised]
PHST- 2024/02/26 00:00 [accepted]
PHST- 2024/03/26 06:45 [medline]
PHST- 2024/03/01 01:22 [pubmed]
PHST- 2024/02/29 19:14 [entrez]
AID - S0006-2952(24)00079-0 [pii]
AID - 10.1016/j.bcp.2024.116096 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2024 Apr;222:116096. doi: 10.1016/j.bcp.2024.116096. Epub 2024 
      Feb 27.