Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation

Abstract

Cardiomyopathies are a leading cause of heart failure and are often caused by mutations in sarcomeric genes, resulting in contractile dysfunction and cellular damage. This may stimulate the production of a robust proinflammatory response. To determine whether myocardial inflammation is associated with cardiac dysfunction in dilated cardiomyopathy (DCM) caused by MYBPC3 mutation, we used the well-characterized cMyBP-C(t/t) mouse model of DCM at 3 months of age. Compared to wild type (WT) mice, DCM mice exhibited significantly decreased fractional shortening (36.4±2% vs. 15.5±1.0%, p < 0.0001) and significantly increased spleen weight (5.3±0.3% vs. 7.2±0.4 mm/mg, p = 0.002). Intriguingly, flow cytometry analysis revealed a significant increase in total (CD45+CD11b+Ly6C−MHCII+F480+) macrophages (6.5±1.4% vs. 14.8±1.4%, p = 0.002) and classically activated (CD45+CD11b+Ly6C−MHCII+F480+CD206−) proinflammatory (M1) macrophages (3.4±0.8% vs. 10.3±1.2%, p = 0.0009) in DCM hearts as compared with WT hearts. These results were further confirmed by immunofluorescence analysis of heart tissue sections. Splenic red pulp (CD11b+Ly6C+MHCIIlowF480hi) macrophages were significantly elevated (2.4±0.1% vs. 1.3±0.1%, p = 0.0001) in DCM compared to WT animals. Serum cytokine analysis in DCM animals exhibited a significant increase (0.65±0.2 vs. 2.175±0.5 pg/mL, p = 0.02) in interleukin (IL)-6 compared to WT animals. Furthermore, RNAseq analysis revealed the upregulation of inflammatory pathways in the DCM hearts. Together, these data indicate a robust proinflammatory response in DCM hearts, likely in response to cellular damage triggered by MYBPC3 mutation and resultant contractile dysfunction.

Cardioprotective effects of α‐cardiac actin on oxidative stress in a dilated cardiomyopathy mouse model

“…Preservation of the mitochondrial electron transport chain, which is the main source of reactive oxygen species and oxidative stress when dysfunctional, is one of the pathways improved by α‐cardiac actin as indicated by the data obtained by the transcriptomic approach. Indeed, several studies have previously suggested a relationship between DCM pathogenesis and oxidative stress . Thus, we examined the impact of α‐cardiac actin on the oxidative stress level in the heart by two approaches using DHE to detect superoxide production and DNA breaks in nuclei and carbonylated proteins by DNPH staining (Figure ).…”

Effects of Single and Combined Losartan and Tempol Treatments on Oxidative Stress, Kidney Structure and Function in Spontaneously Hypertensive Rats with Early Course of Proteinuric Nephropathy

“…Protein carbonyl content (PCOs), a general indicator of protein oxidation, was quantified in the kidney by reaction with 2,4-dinitrophenylhydrazine (2,4-DNPH), as previously shown [17]. Total PCOs were determined from the absorbance at 370 nm using a 2,4-DNPH molar absorption coefficient of 0.022 μM -1 cm -1 , and expressed as nmol/mg protein.…”

Dilated cardiomyopathy

“…The genotype frequently does not equate to phenotype because of environmental epigenetic influences on gene expression. For example, mutations that promote cardiomyocyte damage recruit a pro-inflammatory response promoting remodelling and DCM 147 . Thus, assessment of familial DCM would bene fit from an improved understanding of the influence of environmental and epigenetic factors 148,149 .…”