大鼠神经星型胶质细胞(1-5067);CHI Scientific
Perivascular adipose tissue-derived leptin promotes vascular smooth muscle cell phenotypic switching via
p38 mitogen-activatedprotein kinase in metabolic syndrome rats
Experimental Biology and Medicine 2014; 239: 954–965. DOI: 10.1177/1535370214527903
Hao Li1,2, Ya-Ping Wang3, Li-Na Zhang1 and Gang Tian1
1Department of Cardiovascular Medicine, the First Affiliated Hospital, Xi’an Jiaotong University College of
Medicine, Xi’an, Shaanxi 710061, P.R. China;
2Department of Critical Care Medicine, the First Affiliated Hospital, Xi’an Jiaotong University College of
Medicine,Xi’an, Shaanxi 710061, P.R. China;
3Geriatric Cardiology Department,Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi 710061, P.R. China
Corresponding author: Gang Tian. Email: gangtian36@gmail.com
Abstract
Perivascular adipose tissue (PVAT)-derived leptin is a detrimental adipocytokine and plays a critical role in
the development of cardiovascular diseases in metabolic syndrome (MetS). During vascular remodeling,
vascular smooth muscle cells (VSMCs) undergo phenotypic switching into a synthetic phenotype characterized
by decreased expression of differentiation markers (smooth muscle myosin heavy chain, a-smooth muscle actin,
and calponin) and increased proliferation. We aimed to determine whether PVAT-derived leptin influences VSMC
phenotypic switching and to explore the underlying mechanisms in MetS rats. In vivo, 32 Wistar rats were
divided into two groups that received either a normal diet (control rat) or a high-fat diet (MetS rats). After 16
weeks, rat aortas were stained using hematoxylin–eosin and imaged. VSMC differentiation markers and proliferating
cell nuclear antigen (PCNA), PVAT-derived leptin, aortic leptin receptor (ObR), and p38 mitogen-activated protein
kinase (MAPK) expression were detected. In vitro, aortic VSMCs were incubated with MetS rat PVAT conditioned
medium (PVAT-CM) to mimic in vivo conditions and were pretreated with a p38 MAPK inhibitor (SB 203580) or
leptin antagonist. Differentiation marker expression, including PCNA and p38 MAPK, was detected. MetS rats exhibited
pronounced insulin resistance, hyperglycemia, hyperlipidemia, hypertension, obesity, and an associated increase in
PVAT weight. VSMCs underwent phenotypic switching in MetS rat aorta and contributed to vascular remodeling.
PVAT-derived leptin expression was higher in MetS rats than in control rats (P<0.01). ObRa expression and p38 MAPK
phosphorylation were upregulated in MetS rat aorta. In vitro, VSMCs incubated with MetS rat PVAT-CM underwent
phenotypic switching, associated with increased p38 MAPK phosphorylation. This VSMC phenotypic switching was
inhibited by pretreatment with SB 203580 or a leptin antagonist. These results suggest that in MetS rats, PVAT-
derived leptin promotes VSMC phenotypic switching via a p38 MAPK-dependent pathway to exacerbate vascular
remodeling.