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Published on: June 7, 2013
Pharmacological activation of NO-sensitive guanylyl cyclase ameliorates obesity-induced arterial stiffness
Enkhjargal Budbazar1, Aylin Balmes2, Danielle Elliott1
1Vascular Biology Section, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, USA.
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 [4-6]. 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.
Insights
Activating NO-GC with cinaciguat reduces arterial stiffness by decreasing actin polymerization in vascular smooth muscle cells. This approach may offer a new treatment for cardiovascular disease and dementia linked to arterial stiffness.
Area of Science:
- Cardiovascular Science
- Vascular Biology
- Pharmacology
Background:
- Arterial stiffness is a key risk factor for cardiovascular disease and dementia.
- Decreased NO-sensitive guanylyl cyclase (NO-GC) and pVASP lead to increased actin polymerization and arterial stiffness.
- Targeted therapies for arterial stiffness are currently lacking.
Purpose of the Study:
- To investigate if NO-GC activation with cinaciguat can modulate pVASP and actin polymerization in vascular smooth muscle cells (VSMCs).
- To determine if cinaciguat can prevent obesity-induced arterial stiffness.
Main Methods:
- Administered cinaciguat to high fat, high sucrose diet (HFHS)-fed mice.
- Measured pulse wave velocity, pVASP levels, and actin polymerization (F/G actin ratio) in vivo and in cultured VSMCs.
- Utilized smooth muscle-specific cGKI deletion (cGKISMKO) mice and a cGMP analog (8-Br-cGMP) for mechanistic studies.
Main Results:
- Cinaciguat decreased arterial stiffness (pulse wave velocity) without affecting blood pressure in HFHS mice.
- Cinaciguat increased aortic pVASP levels and decreased actin polymerization in vivo.
- In cultured VSMCs, cinaciguat increased pVASP and decreased actin polymerization, an effect dependent on cGKI and mimicked by 8-Br-cGMP.
Conclusions:
- Pharmacological NO-GC activation effectively reduces obesity-associated arterial stiffness by decreasing VSMC actin hyper-polymerization.
- NO-GC activators represent a promising therapeutic strategy for treating arterial stiffness, an unmet clinical need.
- This approach could potentially benefit patients at risk for cardiovascular disease and dementia.
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