Dataset Information

Fibulin-3 is necessary to prevent cardiac rupture following myocardial infarction.

ABSTRACT: Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibroblasts, with expression highest prior to injury and late post-infarct (from ~ day-28 to week-8). In humans, fibulin-3 was upregulated in left ventricular tissue and plasma of heart failure patients. Fibulin-3 knockout (Efemp1^-/-) and wildtype mice were subjected to experimental myocardial infarction. Fibulin-3 deletion resulted in significantly higher rate of cardiac rupture days 3-6 post-infarct, indicating a weak and poorly formed scar, with severe ventricular remodelling in surviving mice at day-28 post-infarct. Fibulin-3 knockout mice demonstrated less collagen deposition at day-3 post-infarct, with abnormal collagen fibre-alignment. RNA-seq on day-3 infarct tissue revealed upregulation of ECM degradation and inflammatory genes, but downregulation of ECM assembly/structure/organisation genes in fibulin-3 knockout mice. GSEA pathway analysis showed enrichment of inflammatory pathways and a depletion of ECM organisation pathways. Fibulin-3 originates from cardiac fibroblasts, is upregulated in human heart failure, and is necessary for correct ECM organisation/structural integrity of fibrotic tissue to prevent cardiac rupture post-infarct.

SUBMITTER: Murtha LA

PROVIDER: S-EPMC10495317 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Fibulin-3 is necessary to prevent cardiac rupture following myocardial infarction.

Murtha Lucy A LA Hardy Sean A SA Mabotuwana Nishani S NS Bigland Mark J MJ Bailey Taleah T Raguram Kalyan K Liu Saifei S Ngo Doan T DT Sverdlov Aaron L AL Tomin Tamara T Birner-Gruenberger Ruth R Hume Robert D RD Iismaa Siiri E SE Humphreys David T DT Patrick Ralph R Chong James J H JJH Lee Randall J RJ Harvey Richard P RP Graham Robert M RM Rainer Peter P PP Boyle Andrew J AJ

Scientific reports 20230911 1

Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibroblasts, with expression highest prior to injury and late post-infarct (from ~ day-28 to week-8). In humans, fibulin-3 was upregulated in left ventricular ...[more]

PMID: 37696945

Similar Datasets

Project description:BackgroundCardiac rupture (CR) after acute myocardial infarction (AMI) is a fatal mechanical complication. The early identification of factors related to CR in high-risk cases may reduce mortality. The purpose of our study was to discover relevant risk factors for CR after AMI and in-hospital mortality from CR.MethodsIn this study, we enrolled 1,699 AMI cases from October 2013 to May 2020. A total of 51 cases were diagnosed with CR. Clinical diagnostic information was recorded and analyzed retrospectively. We randomly matched these cases with AMI patients without CR in a 1:4 ratio. Univariate and multivariate logistic regression and stratifying analysis were used to identify risk factors for CR. Univariate and multivariate Cox regression hazard analysis and stratifying analysis were used to assess predictors of in-hospital mortality from CR.ResultsThe incidence of CR after AMI was 3.0% and in-hospital mortality was approximately 57%. Multivariate logistic regression analysis identified that white blood cell count, neutrophil percentage, anterior myocardial infarction, a Killip class of >II, and albumin level were independently associated with CR (p < 0.05). Stratifying analysis showed that age, systolic blood pressure, and bicarbonate were independent risk factors for female CR (p < 0.05) but not male CR. Triglyceride and cardiac troponin I were independent risk factors for male CR (p < 0.05) but not female CR. Anterior myocardial infarction, a Killip class of >II, and neutrophil percentage were independent risk factors for male and female CR (p < 0.05). Multivariate Cox regression analysis showed that the time from symptom to CR and the site of CR were independent predictors for in-hospital mortality from CR (p < 0.05). Stratification analysis indicated that risk factors did not differ based on gender, but platelet counts were predictors for in-hospital mortality in female and male CR.ConclusionLow albumin, a high white blood cell count, neutrophil percentage, anterior myocardial infarction, and a Killip class of >II were independent and significant predictors for CR. However, risk factors are different in male and female CR. The time from symptom to CR, the site of CR, and platelet counts were independent predictors for in-hospital mortality from CR. These may be helpful in the early and accurate identification of high-risk patients with CR and the assessment of prognosis. In addition, gender differences should be considered.

Project description:Background The mitochondrial mRNA-binding protein FASTKD1 (Fas-activated serine/threonine [FAST] kinase domain-containing protein 1) protects myocytes from oxidative stress in vitro. However, the role of FASTKD1 in the myocardium in vivo is unknown. Therefore, we developed cardiac-specific FASTKD1 transgenic mice to test the effects of this protein on experimental myocardial infarction (MI). Methods and Results Transgenic mouse lines with cardiac myocyte-specific overexpression of FASTKD1 to varying degrees were generated. These mice displayed normal cardiac morphological features and function at the gross and microscopic levels. Isolated cardiac mitochondria from all transgenic mouse lines showed normal mitochondrial function, ATP levels, and permeability transition pore activity. Male nontransgenic and transgenic mice from the highest-expressing line were subjected to 8 weeks of permanent coronary ligation. Of nontransgenic mice, 40% underwent left ventricular free wall rupture within 7 days of MI compared with 0% of FASTKD1-overexpressing mice. At 3 days after MI, FASTKD1 overexpression did not alter infarct size. However, increased FASTKD1 resulted in decreased neutrophil and increased macrophage infiltration, elevated levels of the extracellular matrix component periostin, and enhanced antioxidant capacity compared with control mice. In contrast, markers of mitochondrial fusion/fission and apoptosis remained unaltered. Instead, transcriptomic analyses indicated activation of the integrated stress response in the FASTKD1 transgenic hearts. Conclusions Cardiac-specific overexpression of FASTKD1 results in viable mice displaying normal cardiac morphological features and function. However, these mice are resistant to MI-induced cardiac rupture and display altered inflammatory, extracellular matrix, and antioxidant responses following MI. Moreover, these protective effects were associated with enhanced activation of the integrated stress response.

Dataset Information

Fibulin-3 is necessary to prevent cardiac rupture following myocardial infarction.

Publications

Fibulin-3 is necessary to prevent cardiac rupture following myocardial infarction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets