Abstract
Angiotensin (Ang) II is the major bioactive peptide of the renin–angiotensin system (RAS); it contributes to the pathogenesis of hypertension by inducing vascular contraction and adverse remodeling, thus elevated peripheral resistance. Ang II also activates Src family kinases (SFK) in the vascular system, which has been implicated in cell proliferation and migration. However, the role of SFK in Ang II-induced hypertension is largely unknown. In this study, we found that administration of a SFK inhibitor SU6656 markedly lowered the level of systemic BP in Ang II-treated mice, which was associated with an attenuated phosphorylation of the smooth-muscle myosin-light-chain (MLC) in the mesenteric resistant arteries. In the cultured human coronary artery smooth muscle cells (SMCs), pretreatment with SU6656 blocked Ang II-induced MLC phosphorylation and contraction. These results for the first time demonstrate that SFK directly regulate vascular contractile machinery to influence BP. Thus our study provides an additional mechanistic link between Ang II and vasoconstriction via SFK-enhanced MLC phosphorylation in SMCs, and suggests that targeted inhibition of Src may provide a new therapeutic opportunity in the treatment of hypertension.
Highlights
Hypertension affects approximately 78 million people in the United States, and is a major risk factor for coronary artery disease, congestive heart failure, stroke, end-stage renal disease, and peripheral vascular disease [1]
SU6656 treatment diminished Ang IIinduced increase in phospho-myosin’s regulatory light chain (MLC) (Fig 2). These results suggest that Src family kinases (SFK) may contribute to Ang II-induced blood pressure (BP) elevation, at least partially, by augmenting MLC phosphorylation; and SFK inhibition attenuates Ang II-induced BP elevation by blunting MLC phosphorylation
We found that Ang II treatment markedly increased Src and MLC phosphorylation and smooth muscle cells (SMCs) contraction, and that these changes were abrogated by pretreatment with SU6656 (Fig 3)
Summary
Hypertension affects approximately 78 million people in the United States, and is a major risk factor for coronary artery disease, congestive heart failure, stroke, end-stage renal disease, and peripheral vascular disease [1]. Current pharmacological therapy of essential hypertension primarily focuses on reducing vascular resistance by antagonizing vasoconstricting peptide hormones, such as Ang II and catecholamines, and calcium channels [2]. Vascular resistance is attributed primarily to the action of the contractile machinery, including actin and myosin filaments, in the vascular SMCs of the resistant vessels. Phosphorylation of the myosin’s regulatory light chain (MLC) subunits, on Serine 19, is a key signaling event, which allows myosin to bind actin and use ATP to generate a force of contraction [3, 4]. The reaction is PLOS ONE | DOI:10.1371/journal.pone.0127891 May 26, 2015
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