Abstract
Marrow stromal cells (MSCs) are in different stages of clinical trials for stroke patients. MSCs are proposed to promote recovery through the release of secretomes that modulate the function of beneficial immune cells. The majority of stroke patients have comorbidities including hypertension, for which they are prescribed antihypertensive medications that might affect the function of MSCs, when they are administered in stroke patients. Here, we studied the effects of common antihypertensive medications on the secretomes of human MSCs and their modulation of human monocytes (Mo) derived from stroke patients. MTT assay was used to assess the proliferation of MSCs after they were exposed to increased levels of antihypertensive medications. MSCs were exposed to the following medications: atenolol, captopril, and losartan. Monocytes were isolated from stroke patients with NIHSS ranging from 11 to 20 and from healthy controls. MSC-Mo cocultures were established, and a secretome profile was analyzed using the Magpix Multiplex cytokine array from Luminex technology. The linear mixed-effect model was used for statistical analysis. All analyses were performed using SAS 9.4, and p values less than 0.05 were considered significant. At clinically relevant levels, there was no change in MSC proliferation after exposure to atenolol, captopril, or losartan. Atenolol increased IL-1RA in stroke-Mo and decreased IL-8 secretion from MSCs indicating an anti-inflammatory effect of atenolol on secretomes of these cells. Captopril increased IL-8 from stroke-Mo and increased IL-6, IL-8, and MCP-1 secretions from MSCs. Captopril also increased IL-6 secretion from cocultures of stroke-Mo and MSCs indicating a strong proinflammatory effect on MSCs and their interaction with Mo. Atenolol increased the secretion of IL-8 and MCP-1 while captopril increased the secretion of IL-6 and MCP-1 from MSCs. Losartan decreased the release of IL-6 from MSCs. Losartan reduced MCP-1 and TNF-α from stroke-Mo and reduced IL-8 from cocultures of stroke-Mo and MSCs. Our results show that antihypertensive medications such as atenolol, captopril, and losartan, at concentrations comparable to doses prescribed for patients hospitalized for acute stroke, modulate the secretome profile of MSCs and their modulatory effects on target immune cells. Our results suggest that stroke trials involving the use of intravenous MSCs should consider the effect of these antihypertensive drugs administered to stroke patients.
Highlights
Stroke is one of the major causes of death and disability around the world
When we subjected mesenchymal stromal cells (MSCs) in our experiment to various doses of atenolol, captopril, and losartan for 24 and 48 hours, we found no significant difference in the proliferation of MSCs at physiologically relevant doses of all three drugs as compared to vehicle controls (Fig S1)
Since intravenously administered MSCs have advanced to clinical trials in stroke patients, we posed clinically relevant questions about the effects of antihypertensive medications commonly taken by hospitalized stroke patients because of preexisting hypertension
Summary
Stroke is one of the major causes of death and disability around the world. Acute stroke is characterized by a sudden increase of inflammation that leads to secondary brain injury. Cell-based therapies [1,2,3,4,5] are under investigation as a treatment for stroke. Patients with an acute ischemic stroke are prescribed medications upon admission to the hospital. Many stroke patients have comorbidities such as hypertension, have elevated blood pressure in the hospital after a stroke, and are prescribed antihypertensive medications such as betablockers, ACE inhibitors, and angiotensive II receptor blockers. The effects of these drugs in altering long-term
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