Cardiovascular disease is a threat to human health and seriously impacts quality of life [
1]. Atherosclerosis (AS) is a major pathological basis of cardiovascular and cerebrovascular diseases [
2]. Although the mechanism underlying AS is complex, the basic pathology of AS is fibrous proliferation caused by the presence of progressive lipid deposits, accumulation of inflammatory cells and deposition of extracellular matrix [
3,
4]. AS is not a separate pathological process; rather, it is regulated by a variety of cells and intracellular signaling pathways [
5]. Smooth muscle cells (SMCs) play an important role in the development of AS [
6,
7].
Protein tyrosine phosphorylation and dephosphorylation play significant roles in numerous intracellular signaling pathways and are influenced by several opposing kinases, such as protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) [
8,
9]. PTKs catalyze tyrosine phosphorylation, whereas PTPs catalyze dephosphorylation [
10]. Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2), also known as protein tyrosine phosphatase N 11 (PTPN11), is an important PTP that acts downstream of various growth factors, cytokines and tyrosine kinases. It plays an integral role in multiple cellular events that regulate various functions, including migration, differentiation, survival and metabolism [
11‐
13]. Schramm found that pharmacological reduction of SHP2/FAK/Akt/mTOR signaling at all levels of the signaling cascade effectively prevents cardiomyocyte hypertrophy [
14]. In recent years, SHP2 inhibitors have become available for research applications. A SHP2 inhibitor phenylhydrazono pyrazolone sulfonate 1 (PHPS1) is a potent and cell permeable inhibitor that is specific for SHP2 over the closely related tyrosine phosphatases SHP1 and PTP1B [
15]. In neutrophils, inflammatory monocytes and pDCs, the level of SHP2 expression is much lower than SHP1 [
16]. PTP1B is an enzyme that negatively regulates insulin signaling and is likely involved in the pathways leading to insulin resistance [
17]. PHPS1 remarkably suppresses E2-induced gene transcription, rapid DNA synthesis and late effects on cell growth. The finding introduces a new mechanism for SHP2 oncogenic action and sheds new light on extranuclear ER-initiated actions in breast cancer [
18]. SHP2 regulates the acute pulmonary inflammation induced by cigarette smoke through the ERK1/2 pathway. PHPS1 significantly inhibits ERK1/2 activation and attenuates the inflammatory response induced in mouse lungs [
19].
The purpose of this study was to determine whether the SHP2 inhibitor PHPS1 has a pro-atherosclerotic or an atheroprotective effect in vivo and in vitro by evaluating the effect of phosphorylation or dephosphorylation on the development of AS in LDL receptor-deficient (Ldlr−/−) mice.