The novel mineralocorticoid receptor antagonist finerenone attenuates neointima formation after vascular injury

<div><p>Background</p><p>The novel nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone holds promise to be safe and efficient in the treatment of patients with heart failure and/or chronic kidney disease. However, its effects on vascular function remain elusive.</p><p>Purpose</p><p>The aim of this study was to determine the functional effect of selective MR antagonism by finerenone in vascular cells <i>in vitro</i> and the effect on vascular remodeling following acute vascular injury <i>in vivo</i>.</p><p>Methods and results</p><p><i>In vitro</i>, finerenone dose-dependently reduced aldosterone-induced smooth muscle cell (SMC) proliferation, as quantified by BrdU incorporation, and prevented aldosterone-induced endothelial cell (EC) apoptosis, as measured with a flow cytometry based caspase 3/7 activity assay.</p><p><i>In vivo</i>, oral application of finerenone resulted in an accelerated re-endothelialization 3 days following electric injury of the murine carotid artery. Furthermore, finerenone treatment inhibited intimal and medial cell proliferation following wire-induced injury of the murine femoral artery 10 days following injury and attenuated neointimal lesion formation 21 days following injury.</p><p>Conclusion</p><p>Finerenone significantly reduces apoptosis of ECs and simultaneously attenuates SMC proliferation, resulting in accelerated endothelial healing and reduced neointima formation of the injured vessels. Thus, finerenone appears to provide favorable vascular effects through restoring vascular integrity and preventing adverse vascular remodeling.</p></div

Blood values in mice treated with vehicle or finerenone.

<p>Blood values in mice treated with vehicle or finerenone.</p

Functional effects of finerenone <i>in vitro</i>.

<p>Human smooth muscle cells (SMC) and human endothelial cells (EC) were incubated either with aldosterone alone or with aldosterone and different concentrations of finerenone, each dissolved in dimethylsulfoxide (DMSO, final concentration 0.1%) for 24 hours. A-D, Cell proliferation was determined by BrdU incorporation assays (n = 10 for SMCs/n = 6 for ECs, *<i>P</i><0.05 to serum-free, #<i>P</i><0.05 to DMSO by ordinary 1way ANOVA followed by multiple comparisons using the Tukey method). E-F, Apoptosis was determined by flow-cytometry-based caspase 3/7 activity measurement (n = 3, **<i>P</i><0.01 to serum-free, #<i>P</i><0.05 and ##<i>P</i><0.01 to DMSO by ordinary 1way ANOVA followed by multiple comparisons using the Tukey method, aldosterone 10 nM was used for B and D-F).</p

Finerenone reduces the intimal and medial leukocyte content.

<p>Wire-induced femoral artery dilation was performed in 10-week-old C57BL/6 mice. Finerenone or vehicle was daily delivered as oral gavage. A, Ten days after injury, leukocyte content was assessed by immunfluorescence staining for the pan-leukocyte marker CD45 (red). Co-immunostaining for CD31 (green) and staining of nuclei with DAPI (blue) was performed to assess the endothelial lining and the overall cell number for better morphological orientation and to allow quantification. B, The amount of leukocytes was determined as the total number of CD45⁺ cells (n = 6, *<i>P</i><0.05, **<i>P</i><0.01 by ordinary 1way ANOVA followed by multiple comparisons using the Tukey method).</p

Finerenone prevents medial and intimal cell proliferation.

<p>Wire-induced femoral artery dilation was performed in 10-week-old C57BL/6 mice. Finerenone or vehicle was daily delivered as oral gavage. A, Ten days after injury, cell proliferation was assessed by immunfluorescence staining for DAPI (blue), α-smooth muscle actin (α-SMA, red), and Ki-67 (green). B, The amount of proliferating cells was determined as Ki-67⁺ cells/DAPI⁺ cells (n = 6, **P<0.01, ***P<0.001 by ordinary 1way ANOVA followed by multiple comparisons using the Tukey method).</p

Finerenone promotes early endothelial recovery.

<p>Electrical denudation of the carotid artery was performed in 10 weeks old C57BL/6J mice. Finerenone or vehicle was daily delivered as oral gavage. A, Three days following injury, endothelial regeneration was evaluated by injection of a 5% Evan’s blue solution and en face microscopy. B, The re-endothelialized distance was calculated by substraction of the deendothelialized distance from 4 mm (standardized denudated area, n = 9, **<i>P</i><0.01 by ordinary 1way ANOVA followed by multiple comparisons using the Tukey method).</p

Table_1_Premature stroke and cardiovascular risk in primary Sjögren's syndrome.DOCX

IntroductionPrimary Sjögren's syndrome (pSS) is associated with an increased prevalence of traditional risk factors and cardiovascular diseases (CVDs). The study aimed to identify specific risk factors for CVD in pSS patients.MethodsPSS patients with and without CVD were compared. All patients fulfilled the EULAR/ACR classification criteria. Patients with CVD presented at least one of the following manifestations: myocardial infarction, transient ischemic attacks, ischemic or hemorrhagic stroke, peripheral artery disease, coronary artery disease, and carotid plaques. Data were collected by a standardized protocol and review of medical records.Results61/312 (19.6%) pSS patients presented with CVD. Traditional risk factors such as hypertension, hypercholesterinemia and diabetes (p ConclusionRaynaud's phenomen as well as vasculitis and high ESSDAI have shown a significant association to CVD. PSS patients with cerebrovascular events were younger than expected. Knowledge about risk factors may help clinicians to identify pSS patients at risk for CVD. After diagnosis of pSS, patients should be screened for risk factors such as hypertension and receive appropriate therapy to prevent or at least reduce sequelae such as infarction. However, further investigations are necessary in order to achieve a reliable risk stratification for these patients.</p