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Nitro-Oleic Acid (NO2-OA) Improves Systolic Function in Dilated Cardiomyopathy by Attenuating Myocardial Fibrosis.

ABSTRACT: Nitro-oleic acid (NO2-OA), a nitric oxide (NO)- and nitrite (NO2-)-derived electrophilic fatty acid metabolite, displays anti-inflammatory and anti-fibrotic signaling actions and therapeutic benefit in murine models of ischemia-reperfusion, atrial fibrillation, and pulmonary hypertension. Muscle LIM protein-deficient mice (Mlp-/-) develop dilated cardiomyopathy (DCM), characterized by impaired left ventricular function and increased ventricular fibrosis at the age of 8 weeks. This study investigated the effects of NO2-OA on cardiac function in Mlp-/- mice both in vivo and in vitro. Mlp-/- mice were treated with NO2-OA or vehicle for 4 weeks via subcutaneous osmotic minipumps. Wildtype (WT) littermates treated with vehicle served as controls. Mlp-/- mice exhibited enhanced TGFβ signalling, fibrosis and severely reduced left ventricular systolic function. NO2-OA treatment attenuated interstitial myocardial fibrosis and substantially improved left ventricular systolic function in Mlp-/- mice. In vitro studies of TGFβ-stimulated primary cardiac fibroblasts further revealed that the anti-fibrotic effects of NO2-OA rely on its capability to attenuate fibroblast to myofibroblast transdifferentiation by inhibiting phosphorylation of TGFβ downstream targets. In conclusion, we demonstrate a substantial therapeutic benefit of NO2-OA in a murine model of DCM, mediated by interfering with endogenously activated TGFβ signaling.

SUBMITTER: Braumann S

PROVIDER: S-EPMC8396484 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Nitro-Oleic Acid (NO2-OA) Improves Systolic Function in Dilated Cardiomyopathy by Attenuating Myocardial Fibrosis.

Braumann Simon S Schumacher Wibke W Im Nam Gyu NG Nettersheim Felix Sebastian FS Mehrkens Dennis D Bokredenghel Senai S Hof Alexander A Nies Richard Julius RJ Adler Christoph C Winkels Holger H Knöll Ralph R Freeman Bruce A BA Rudolph Volker V Klinke Anna A Adam Matti M Baldus Stephan S Mollenhauer Martin M Geißen Simon S

International journal of molecular sciences 20210822 16

Nitro-oleic acid (NO2-OA), a nitric oxide (NO)- and nitrite (NO2-)-derived electrophilic fatty acid metabolite, displays anti-inflammatory and anti-fibrotic signaling actions and therapeutic benefit in murine models of ischemia-reperfusion, atrial fibrillation, and pulmonary hypertension. Muscle LIM protein-deficient mice (Mlp-/-) develop dilated cardiomyopathy (DCM), characterized by impaired left ventricular function and increased ventricular ...[more]

PMID: 34445757

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Project description:Ventral hernia is often addressed surgically by the placement of prosthetic materials, either synthetic or from allogeneic and xenogeneic biologic sources. Despite advances in surgical approaches and device design, a number of postsurgical limitations remain, including hernia recurrence, mesh encapsulation, and reduced vascularity of the implanted volume. The in situ controlled release of angiogenic factors from a scaffold facilitating abdominal wall repair might address some of these issues associated with suboptimal tissue reconstruction. Furthermore, a biocomposite material that combines the favorable mechanical properties achievable with synthetic materials and the bioactivity associated with xenogeneic tissue sources would be desirable. In this report, an abdominal wall repair scaffold has been designed based on a microfibrous, elastomeric poly(ester carbonate)urethane urea matrix integrated with a hydrogel derived from decellularized porcine dermis (extracellular matrix [ECM] gel) and poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with nitro-oleic acid (NO2-OA). NO2-OA is an electrophilic fatty acid nitro-alkene derivative that, under hypoxic conditions, induces angiogenesis. This scaffold was utilized to repair a rat abdominal wall partial thickness defect, hypothesizing that the nitro-fatty acid release would facilitate increased angiogenesis at the 8-week endpoint. The quantification of neovascularization was conducted by novel methodologies to assess vessel morphology and spatial distribution. The repaired abdominal wall defects were evaluated by histopathologic methods, including quantification of the foreign body response and cellular ingrowth. The results showed that NO2-OA release was associated with significantly improved regional angiogenesis. The combined biohybrid scaffold and NO2-OA-controlled release strategy also reduced scaffold encapsulation, increased wall thickness, and enhanced cellular infiltration. More broadly, the three components of the composite scaffold design (ECM gel, polymeric fibers, and PLGA microparticles) enable the tuning of performance characteristics, including scaffold bioactivity, degradation, mechanics, and drug release profile, all decisive factors to better address current limitations in abdominal wall repair or other soft tissue augmentation procedures.

Project description:BackgroundAmong patients with dilated cardiomyopathy (DCM), myocardial inflammation and fibrosis are risk factors for poor clinical outcomes. Here, we investigated the combined prognostic value of these two factors, as evaluated using myocardial biopsy samples.MethodsThis retrospective and multicentre study included patients with DCM-defined as LVEF of ≤45% and left diastolic diameter of >112% of predicted value, without evidence of secondary or ischaemic cardiomyopathy. In myocardial biopsy samples, inflammatory cells were counted using immunohistochemistry, and Masson's Trichrome staining was performed to quantify the myocardial fibrosis as collagen area fraction (CAF). Higher myocardial inflammation was defined as leucocytes of ≥14/mm², including ≤4 monocytes/mm², with CD3+ T lymphocytes of≥7/mm². Greater myocardial fibrosis was defined as CAF of>5.9% by the Youden's index. The primary endpoint was cardiac death or left ventricular assist device implantation.ResultsA total of 255 DCM patients were enrolled (average age, 53.1 years; 78% males). Within this cohort, the mean LVEF was 28.0%, mean CAF was 10.7% and median CD3+ cell count was 8.3/mm2. During the median follow-up period of 2688 days, 46 patients met the primary endpoint. Multivariable Cox proportional hazard analyses revealed that CD3+ cell count and CAF were independent determinants of the primary endpoint. Kaplan-Meier analysis showed that patients with both higher myocardial inflammation and greater fibrosis had the worst prognosis (log-rank p<0.001). When myocardial inflammation was graded as one of three degrees: T lymphocytes of <13/mm² (low); 13 of 13.1-23.9/mm² (moderate); and T lymphocytes of ≥24 /mm² (high), patients with moderate inflammation exhibited a superior survival rate when CAF was ≤5.9%, but a worse survival rate when CAF was >5.9%.ConclusionsHaving both biopsy-proven higher myocardial inflammation and greater fibrosis predicted the worst clinical prognosis in patients with DCM.

Dataset Information

Nitro-Oleic Acid (NO2-OA) Improves Systolic Function in Dilated Cardiomyopathy by Attenuating Myocardial Fibrosis.

Publications

Nitro-Oleic Acid (NO<sub>2</sub>-OA) Improves Systolic Function in Dilated Cardiomyopathy by Attenuating Myocardial Fibrosis.

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