Opioids Cause Vascular Remodeling via Changes in Cofilin‐ERK Signaling: Female Mice Present Higher Risk of Developing Morphine‐induced Cardiovascular Disease than Male Mice

Abstract

According to the most recent CDC Annual Surveillance Report of Drug Related Risks and Outcomes, more than 47,600 people died from an opioid overdose in 2017 in the United States. The magnitude of the national crisis raises questions on intersecting points between opioid abuse and the main systems of the human body. Recent statistical analyses have shown that chronic use of prescription or illicit opioids leads to an increased risk of a cardiovascular event, which was higher among women than men. We hypothesized that chronic exposure to exogenous opioids causes sex‐specific vascular remodeling via changes in actin polymerization, leading to an increased risk of cardiovascular disease. In a preliminary study to test our hypothesis, we observed that treatment with the exogenous opioid morphine (≥ 24 hours) induced vascular smooth muscle cell proliferation. Acknowledging the emerging roles of cofilins and extracellular signal‐regulated kinases (ERK) in the regulation of cell proliferation by mediating actin dynamics, we investigated the effects of morphine (MOR) on the intracellular levels of both proteins in vasculature. Mesenteric resistance arteries (MRA) from 10 week old wild type C57BL/6NTac male and female mice were extracted (n=4). The MRA of each animal were isolated and divided equally into control and treatment groups. The control and treated samples were incubated in DMEM with 1% penicillin‐streptomycin at 37°C for 24 hours in the absence or presence of MOR (1μM) respectively. We observed that MOR increased phosphorylated/inactivated cofilin 1.6 fold [arbitrary units (AU), control: 0.59 ± 0.14 vs MOR: 0.95 ± 0.10*, *p<0.05] and increased phosphorylated/activated ERK 1.8 fold (AU, control: 0.51 ± 0.11 vs MOR: 0.90 ± 0.13*, *p<0.05) in the MRA from female mice. On the other hand, MOR decreased phosphorylated ERK 1.5 fold (AU, control: 0.91 ± 0.08 vs MOR: 0.59 ± 0.11*, *p<0.05) but had no effect on the levels of phosphorylated cofilin (p>0.05) in the MRA from male mice. Our data suggest that exogenous opioids change actin dynamics in arteries from both male and female mice. Further, this study is the first to demonstrate that prolonged exposure to morphine may increase cardiovascular risk in females when compared to males.Support or Funding InformationThis work was supported by National Institutes of Health (NIH) (NIH: R00GM118885).Levels of phosphorylated cofilin (left) and ERK (right) in MRA from male and female mice after 24 hours of treatment with morphine (MOR, 1μM) or vehicle.Figure 1