Enkhjargal Budbazar , Aylin Balmes , Danielle Elliott , Lisette Peres Tintin , Timo Kopp , Susanne Feil , Robert Feil , Tilman E. Schäffer , Francesca Seta
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引用次数: 0
Abstract
Background & purpose
Arterial stiffness, or loss of elastic compliance in large arteries, is an independent precursor of cardiovascular disease (CVD) [1] and dementia [2] for which currently there are no targeted therapies. We previously discovered that decreases in NO-sensitive guanylyl cyclase (NO-GC), the NO receptor which synthesizes cGMP, and in its target vasodilator-stimulated phosphoprotein (pVASPS239), lead to increased cytoskeletal actin polymerization in vascular smooth muscle cells (VSMCs) contributing to increased arterial stiffness [3]. In the current study, we tested whether activating NO-GC with an NO-GC activator (cinaciguat) modulates pVASPS239 and cytoskeletal actin polymerization in VSMCs, thereby preventing obesity-induced arterial stiffness.
Experimental approach & key results
Cinaciguat administration (5 mg/kg) to high fat, high sucrose diet (HFHS)-fed mice, our established model of arterial stiffness [4], (1) decreased pulse wave velocity, the in vivo index of arterial stiffness, without affecting blood pressure; (2) increased aortic pVASPS239 levels; and (3) decreased actin polymerization, measured as ratio of filamentous (F) to globular (G) actin, compared to vehicle administration. In cultured VSMCs, cinaciguat (10 μmol/L) increased pVASPS239 levels and decreased the F/G actin ratio at baseline and after stimulation with the cytokine tumor necrosis factor α (TNFα), which we previously showed is significantly increased in the aorta of HFHS-fed mice [[4], [5], [6]]. These effects were abrogated in aortas and VSMCs from mice with smooth muscle-specific cGKI deletion (cGKISMKO), while being mimicked by a cell-permeable cGMP analog (8-Br-cGMP), which also decreased VSMC stiffness in vitro.
Conclusions & implications
Collectively, our data strongly support the notion that pharmacological NO-GC activation would be beneficial in decreasing obesity-associated arterial stiffness by decreasing VSMC cytoskeletal actin hyper-polymerization. If translated to humans, NO-GC activators could become a viable approach to clinically treat arterial stiffness, which remains an unmet medical need.
期刊介绍:
Vascular Pharmacology publishes papers, which contains results of all aspects of biology and pharmacology of the vascular system.
Papers are encouraged in basic, translational and clinical aspects of Vascular Biology and Pharmacology, utilizing approaches ranging from molecular biology to integrative physiology. All papers are in English.
The Journal publishes review articles which include vascular aspects of thrombosis, inflammation, cell signalling, atherosclerosis, and lipid metabolism.