Role of nifedipine and hydrochlorothiazide in MAPK activation and vascular smooth muscle cell proliferation and apoptosis.
BACKGROUND
Once hypertension is established, increased mechanical stretch stress becomes a leading cause of vascular remodeling. Clinical antihypertension guidelines demonstrate that antihypertension drugs prevent vascular remodeling in hypertensive patients mainly by lowering blood pressure, suggesting an indirect way of reducing the effects of stretch stress (hypertension). Whether these drugs can directly block the effects of the stretch stress on vascular remodeling has not been reported to date. This study was designed to answer this question and explore the underlying mechanisms.


METHODS
Cultured quiescent vascular smooth muscle cells (VSMCs) were stimulated by stretch stress after pretreatment with nifedipine and hydrochlorothiazide. The phosphorylation levels of extracellular signal-regulated kinases (ERKs), c‑Jun NH2-terminal protein kinases (JNKs), and p38 mitogen-activated protein kinase (MAPK) in VSMCs were detected via Western blotting. The treated cells were stained using triple-labeled immunofluorescence with Ki67 antibody and a TUNEL kit in the presence of DAPI for the detection of proliferative, apoptotic, and resting cells.


RESULTS
Compared with the negative control, both nifedipine and hydrochlorothiazide had no influence on the phosphorylation of MAPKs and on the proliferation and apoptosis of VSMCs in resting state. Stretch stress could significantly induce increased phosphorylation of MAPKs as well as proliferation and apoptosis of VSMCs. Nifedipine inhibited the effects of stretch stress in a dose-dependent manner. Contrary to the effects of nifedipine, hydrochlorothiazide synergistically amplified the effects induced by stretch stress.


CONCLUSIONS
Nifedipine and hydrochlorothiazide have opposing functions in the increased phosphorylation of MAPK and in the proliferation and apoptosis of VSMCs induced by stretch stress. The former plays a role as an inhibitor, while the latter functions as a promoter.
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, 74# Zhongshan Road 2, 510089, Guangzhou, China.
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Wang
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, 74# Zhongshan Road 2, 510089, Guangzhou, China.
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Liu
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, 74# Zhongshan Road 2, 510089, Guangzhou, China.
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Wang
Departments of Orthopedic Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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Li
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, 74# Zhongshan Road 2, 510089, Guangzhou, China.
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Y
Li
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, 74# Zhongshan Road 2, 510089, Guangzhou, China.
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S
Ping
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, 74# Zhongshan Road 2, 510089, Guangzhou, China.|Department of Clinic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
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ASA
Bardeesi
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, 74# Zhongshan Road 2, 510089, Guangzhou, China.|Department of Clinic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
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Y
Guo
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, 74# Zhongshan Road 2, 510089, Guangzhou, China.
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Y
Zhou
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, 74# Zhongshan Road 2, 510089, Guangzhou, China.
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T
Pei
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, 74# Zhongshan Road 2, 510089, Guangzhou, China.
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L
Deng
Departments of Orthopedic Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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P
Sheng
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, 74# Zhongshan Road 2, 510089, Guangzhou, China. liushuy3@mail.sysu.edu.cn.
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S
Liu
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, 74# Zhongshan Road 2, 510089, Guangzhou, China. lichaoh@mail.sysu.edu.cn.
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Li
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006852:Hydrochlorothiazide / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology*; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000503:physiopathology; D009543:Nifedipine / Q000494:pharmacology*; D010766:Phosphorylation; D066253:Vascular Remodeling / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D006852:Hydrochlorothiazide; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D009543:Nifedipine
Hydrochlorothiazide; MAPK phosphorylation; Muscle, smooth, vascular; Nifedipine; Stress, mechanical