Ectopic trypsin in the myocardium promotes dilated cardiomyopathy after influenza A virus infection

2014 ◽  
Vol 307 (6) ◽  
pp. H922-H932 ◽  
Author(s):  
Hai-Yan Pan ◽  
Hua-Mei Sun ◽  
Lu-Jing Xue ◽  
Min Pan ◽  
Yi-Ping Wang ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Dilated Cardiomyopathy ◽  
Influenza A Virus ◽  
Trypsin Inhibitor ◽  
Influenza A ◽  
Collagen Type ◽  
Collagen Type I ◽  
Left Ventricular ◽  
Type I ◽  
Ventricular Dilation

We have previously reported that ectopic trypsin in the myocardium triggers acute myocarditis after influenza A virus (IAV) infection. As myocarditis is a common precursor to dilated cardiomyopathy (DCM), the aim of the present study was to investigate the influence of trypsin on the progression of DCM after IAV infection. IAV-infected mice treated with saline or trypsin inhibitor were euthanized on days 0, 9, 20, 40 and 60 postinfection. Trypsin expression colocalized with myocardial inflammatory loci and IAV-induced myocarditis peaked on day 9 postinfection and alleviated by day 20 but persisted until day 60 postinfection, even though replication of IAV was not detected from day 20 postinfection. Similar time courses were observed for the activation of pro-matrix metalloproteinase (pro-MMP)-9 and expression of the proinflammatory cytokines IL-6, IL-1β, and TNF-α. Degradation of collagen type I, proliferation of ventricular interstitial collagen, and expression of collagen type I and III mRNA increased significantly during acute and chronic phases; collagen type III mRNA increased more significantly than collagen type I mRNA. Cardiac function progressively deteriorated with progressive left ventricular dilation. The trypsin inhibitor aprotinin suppressed pro-MMP-9 activation and cytokine release, alleviated myocardial inflammation, and restored collagen metabolism during acute and chronic phases of myocarditis. This effectively prevented ventricular dilation and improved cardiac function. These results suggest that ectopic trypsin in the myocardium promoted DCM through chronic activation of pro-MMP-9, persistent induction of cytokines, and mediation of collagen remodeling. Pharmacological inhibition of trypsin activity might be a promising approach for the prevention of viral cardiomyopathy.

scholarly journals Dilated Cardiomyopathy Is Associated With Significant Changes in Collagen Type I/III ratio

Circulation ◽  
1999 ◽  
Vol 99 (21) ◽  
pp. 2750-2756 ◽  
Author(s):  
Matthias Pauschinger ◽  
Dagmar Knopf ◽  
Simone Petschauer ◽  
Andrea Doerner ◽  
Wolfgang Poller ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Collagen Type ◽  
Collagen Type I ◽  
Type I

Glycation end-product cross-link breaker reduces collagen and improves cardiac function in aging diabetic heart

2003 ◽  
Vol 285 (6) ◽  
pp. H2587-H2591 ◽  
Author(s):  
Jing Liu ◽  
Malthi R. Masurekar ◽  
Dorothy E. Vatner ◽  
Garikiparthy N. Jyothirmayi ◽  
Timothy J. Regan ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Cardiac Function ◽  
Protein Content ◽  
Aortic Stiffness ◽  
Collagen Type ◽  
Collagen Type I ◽  
Type I ◽  
Cross Link ◽  
Aging Heart ◽  
Lv Ejection Fraction

Aging and diabetes mellitus (DM) both affect the structure and function of the myocardium, resulting in increased collagen in the heart and reduced cardiac function. As part of this process, hyperglycemia is a stimulus for the production of advanced glycation end products (AGEs), which covalently modify proteins and impair cell function. The goals of this study were first to examine the combined effects of aging and DM on hemodynamics and collagen types in the myocardium in 12 dogs, 9–12 yr old, and second to examine the effects of the AGE cross-link breaker phenyl-4,5-dimethylthazolium chloride (ALT-711) on myocardial collagen protein content, aortic stiffness, and left ventricular (LV) function in the aged diabetic heart. The alloxan model of DM was utilized to study the effects of DM on the aging heart. DM induced in the aging heart decreased LV systolic function (LV ejection fraction fell by 25%), increased aortic stiffness, and increased collagen type I and type III protein content. ALT-711 restored LV ejection fraction, reduced aortic stiffness and LV mass with no reduction in blood glucose level (199 ± 17 mg/dl), and reversed the upregulation of collagen type I and type III. Myocardial LV collagen solubility (%) increased significantly after treatment with ALT-711. These data suggest that an AGE cross-link breaker may have a therapeutic role in aged patients with DM.

scholarly journals Fibrosis biomarkers as a predictive tool for clinical outcome in PLNR14Del patients

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
SM Van Der Voorn ◽  
M Bourfiss ◽  
ASJM Te Riele ◽  
K Taha ◽  
MA Vos ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Clinical Data ◽  
Collagen Type ◽  
Collagen Type I ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Blood Collection ◽  
Type I ◽  
T Wave ◽  
Wave Inversion

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Netherlands Cardio Vascular Research Initiative (CVON): the Dutch heart foundation Background Mutations in phospholamban (PLN, most often PLNR14Del), a protein that regulates Ca2+ homeostasis in cardiomyocytes, are found in patients diagnosed with arrhythmogenic (ACM) and dilated cardiomyopathy (DCM). Fibrosis formation in the heart is one of the hallmarks in PLN patients, which compromises cardiac contractility and predisposes to arrhythmogenicity. Collagen type I is the most abundant type of collagen in the heart (85%). During continuous collagen synthesis propeptides, like procollagen type I carboxy-terminal propeptide (PICP) and during collagen breakdown, C-terminal telopeptide collagen type I (ICTP), are released into the circulation. Clinically, detection of fibrosis occurs via echo or MRI, however difficulties arise when patchy fibrosis has to be detected. Purpose To investigate if PICP and ICTP levels in blood are useful predictive biomarkers for clinical outcome in PLN patients. Methods 78 serum and EDTA blood samples were collected on the same day from ACM diagnosed (n = 12), DCM diagnosed (n = 14) or non-classified (n = 52) PLN patients. PICP levels were measured with an ELISA assay and ICTP with a RIA. Clinical data were subtracted two years around blood collection from Redcap, a Dutch database with medical records from PLN patients. Data were not normally distributed, so Spearman’s correlation coefficient and Mann-Whitney test were used. Results Gender, age and PICP/ICTP ratios were similarly distributed between the subgroups. First, we checked if clinical data subtracted two years around blood collection provided reliable results regarding clinical outcome. Patients who underwent clinical testing  5.5 weeks around blood collection revealed that clinical data were in line with the best-fitted line of the linear regression and therefore provide reliable results. Next, the potential correlation of fibrosis biomarkers with electrical parameters was assessed. Increased PICP/ICTP ratios suggest a higher collagen deposition. Although there was no correlation with prolonged QRS duration (Rs 0.13, n = 62, ns), subgroup analysis showed a significant weak correlation for non-classified patients (Rs 0.32, n = 38, p = 0.05). No significant correlation was found for ACM or DCM patients; however, groups were rather small. PICP/ICTP ratio was significantly higher in patients with T wave inversion and premature ventricular contractions (PVCs) during an exercise tolerance test. A weak inverted correlation was found with left ventricular ejection fraction and PICP/ICTP (Rs -0.28, n = 23, ns), while moderate correlations between the ratio and end diastolic volume, and end systolic volume exist (both Rs 0.40, n = 23, p = 0.06). Conclusion High PICP/ICTP ratios correlate with clinical outcome in PLN patients, such as T wave inversion and PVCs. However, the size and heterogeneity of the patient group resulted in weak to moderate correlation coefficients and might therefore currently precludes to use PICP and ICTP levels as biomarker.

scholarly journals Differential myocardial abundance of collagen type I and type III mRNA in dilated cardiomyopathy: effects of myocardial inflammation

1998 ◽  
Vol 37 (1) ◽  
pp. 123-129 ◽  
Author(s):  
Matthias Pauschinger ◽  
Andrea Doerner ◽  
Andrew Remppis ◽  
Roman Tannhäuser ◽  
Uwe Kühl ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Collagen Type ◽  
Collagen Type I ◽  
Myocardial Inflammation ◽  
Type I ◽  
Type Iii

scholarly journals HMGB1 Aggravates Pressure Overload-Induced Left Ventricular Dysfunction by Promoting Myocardial Fibrosis

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Lei Zhang ◽  
Ying Yu ◽  
Peng Yu ◽  
Jian Wu ◽  
Aijun Sun ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Collagen Type ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
High Mobility ◽  
Collagen Type I ◽  
Left Ventricular ◽  
Type I ◽  
Lv Dysfunction

Aim. Fibrosis had important effects on pressure overload-induced left ventricular (LV) dysfunction. High-mobility group box 1 (HMGB1), which was closely associated with fibrosis, was involved in the pressure overload-induced cardiac injury. This study determines the role of HMGB1 in LV dysfunction under pressure overload. Methods. Transverse aortic constriction (TAC) operation was performed on male C57BL/6J mice to build the model of pressure overload, while HMGB1 or PBS was injected into the LV wall. Cardiac function, collagen volume, and relevant genes were detected. Results. Echocardiography demonstrated that the levels of LV ejection fraction (LVEF) were markedly decreased on day 28 after TAC, which was consistent with raised collagen in the myocardium. Moreover, we found that the exposure of mice to TAC + HMGB1 is associated with higher mortality, BNP, and collagen volume in the myocardium and lower LVEF. In addition, real-time PCR showed that the expression of collagen type I, TGF-β, and MMP2 markedly increased in the myocardium after TAC, while HMGB1 overexpression further raised the TGF-β expression but not collagen type I and MMP2 expressions. Conclusion. This study indicated that exogenous HMGB1 overexpression in the myocardium aggravated the pressure overload-induced LV dysfunction by promoting cardiac fibrosis, which may be mediated by increasing the TGF-β expression.

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