Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities

Ong, Sang‐Bing; Hernández‐Reséndiz, Sauri; Crespo-Avilan, Gustavo E.; Mukhametshina, Regina T.; Kwek, Xiu Yi; Cabrera-Fuentes, Héctor A.; Hausenloy, Derek J.

doi:10.1016/j.pharmthera.2018.01.001

Cited by 612 publications

(548 citation statements)

References 154 publications

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“…Cardiac fibroblasts are central mediators of wound healing and cardiac function after myocardial infarction [16, 49, 54], yet the complexity of the dynamic in vivo paracrine environment and the fibroblast intracellular signaling network hinders therapeutic targeting [55]. Here, we extended a large-scale computational model of the fibroblast signaling network to identify paracrine and intracellular drivers of extracellular matrix synthesis in specific phases of post-infarct healing.…”

Section: Discussionmentioning

confidence: 99%

Computational Model Predicts Paracrine and Intracellular Drivers of Fibroblast Phenotype After Myocardial Infarction

Zeigler

Nelson

Chandrabhatla

et al. 2019

Preprint

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2The fibroblast is a key mediator of wound healing in the heart and other organs, yet how 2 3 it integrates multiple time-dependent paracrine signals to control extracellular matrix 2 4 synthesis has been difficult to study in vivo. Here, we extended a computational model to 2 5 simulate the dynamics of fibroblast signaling and fibrosis after myocardial infarction in 2 6 response to time-dependent data for nine paracrine stimuli. This computational model 2 7was validated against dynamic collagen expression and collagen area fraction data from 2 8 post-infarction rat hearts. The model predicted that while many features of the fibroblast 2 9 phenotype at inflammatory or maturation phases of healing could be recapitulated by 3 0 single static paracrine stimuli (interleukin-1 and angiotensin-II, respectively), mimicking 3 1 of the proliferative phase required paired stimuli (e.g. TGFβ and angiotensin-II). Virtual 3 2 overexpression screens with static cytokine pairs and after myocardial infarction 3 3 predicted phase-specific regulators of collagen expression. Several regulators increased 3 4 (Smad3) or decreased (Smad7, protein kinase G) collagen expression specifically in the 3 5 proliferative phase. NADPH oxidase overexpression sustained collagen expression from 3 6 proliferative to maturation phases, driven by TGFβ and endothelin positive feedback 3 7 loops. Interleukin-1 overexpression suppressed collagen via NFκB and BAMBI (BMP 3 8 and activin membrane-bound inhibitor) incoherent feedforward loops, but it then later 3 9 sustained collagen expression due to the TGFβ positive feedback loop. These model-4 0 based predictions reveal network mechanisms by which the dynamics of paracrine stimuli 4 1 and interacting signaling pathways drive the progression of fibroblast phenotypes and 4 2 fibrosis after myocardial infarction. 4 3 4 4 4 5Wound healing is a complex process that involves a dynamic interplay between 4 6 inflammatory and proliferative signaling. This process is especially important following 4 7 injury to the heart, where cardiomyocytes are unable to regenerate. Scar formation and 4 8 the preservation of viable heart muscle are important for continued cardiac function[1]. 4 9 8 1 understanding how fibroblasts respond during the different phases of wound healing 8 2 could identify mechanisms by which fibrosis develops in other organs. 8 3 Myocardial infarct healing is notoriously difficult to investigate because it 8 4 involves many dynamic and interacting signaling processes. Fibroblasts are particularly 8 5 difficult to study in situ during wound healing because they can differentiate from many 8 6 different cell types and there is no clear consensus on fibroblast markers[20].8 7Computational modeling has been a useful method for investigating complex dynamic 8 8 processes in many areas of biology. Although models have been constructed to study the 8 9 wound healing process post-MI[21], no such model has yet been applied to study 9 0 5 fibroblast intracellular signaling and phenotypic changes during m...

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Section: Discussionmentioning

confidence: 99%

Computational Model Predicts Paracrine and Intracellular Drivers of Fibroblast Phenotype After Myocardial Infarction

Zeigler

Nelson

Chandrabhatla

et al. 2019

Preprint

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“…As shown by our study, inflammation can rapidly and dose-dependently induce increased epidermal green AF, suggesting that the green AF may be used as a novel biomarker for rapid detection of systemic inflammation. Inflammation is a key pathological factor of numerous diseases (9, 12,16,18). However, so far there has been no non-invasive method for determining the levels of systemic inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Inflammation is a crucial pathological factor in multiple major diseases including cerebral ischemia (18), acute myocardial infarction (16), stable coronary artery disease (9), Parkinson's disease (15) and lung cancer (12). Because inflammation can lead to increased levels of cytokines and oxidative stress (7), we proposed our hypothesis that inflammation may also induce increased epidermal green AF.…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide (LPS) induces increased epidermal green autofluorescence of mouse

Tao

et al. 2018

Preprint

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Our recent studies have suggested that characteristic 'Pattern of Autofluorescence (AF)' of each disease could be a novel biomarker for non-invasive diagnosis of multiple major diseases such as acute ischemic stroke. It is necessary to determine if increased epidermal green AF may be produced by major pathological factors such as inflammation. In our current study, we used C57BL/6Slac mice exposed to LPS to test our hypothesis that inflammation may induce increased epidermal green AF: LPS rapidly induced significant increases in the epidermal green AF of the mice's ears at 1 hr after LPS injection. LPS also dose-dependently increased the epidermal green AF. The AF intensity had a linear relationship with the LPS dosages at both 3 and 7 days after the LPS administration. The AF images exhibited the characteristic structure of the keratinocytes in Stratum Spinosum, suggesting that the origin of the increased AF was keratin 1 and/or keratin 10.Collectively, our current study has provided the first evidence indicating that inflammation can rapidly and dose-dependently induce increased epidermal green AF, suggesting that the green AF may be the first biomarker for non-invasive and rapid detection of systemic inflammation. Since inflammation is a key pathological factor of numerous diseases, our finding has highlighted the value of the epidermal AF as a novel diagnostic biomarker for numerous diseases.

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“…To date, most experimental models have been limited because they are based on models where age, gender and genetic background are highly standardized. This is never sufficient in characterizing the progression of diseases that affect patients who are mostly older and have co-morbidities [141]. What will be needed is a “higher resolution” view of the kinetics of immune cells over time in different strains of animals, particularly during dynamic inflammatory states in areas of the heart and body beyond those directly affected by an infarction.…”

Section: Conclusion and Future Directionmentioning

confidence: 99%

Inflammatory cells and their non-coding RNAs as targets for treating myocardial infarction

2018

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Myocardial infarction triggers infiltration of several types of immune cells that coordinate both innate and adaptive immune responses. These play a dual role in post-infarction cardiac remodeling by initiating and resolving inflammatory processes, which needs to occur in a timely and well-orchestrated way to ensure a reestablishment of normalized cardiac functions. Thus, therapeutic modulation of immune responses might have benefits for infarct patients. While such strategies have shown great potential in treating cancer, applications in the post-infarction context have been disappointing. One challenge has been the complexity and plasticity of immune cells and their functions in cardiac regulation and healing. The types appear in patterns that are temporally and spatially distinct, while influencing each other and the surrounding tissue. A comprehensive understanding of the immune cell repertoire and their regulatory functions following infarction is sorely needed. Processes of cardiac remodeling trigger additional genetic changes that may also play critical roles in the aftermath of cardiovascular disease. Some of these changes involve non-coding RNAs that play crucial roles in the regulation of immune cells and may, therefore, be of therapeutic interest. This review summarizes what is currently known about the functions of immune cells and non-coding RNAs during post-infarction wound healing. We address some of the challenges that remain and describe novel therapeutic approaches under development that are based on regulating immune responses through non-coding RNAs in the aftermath of the disease.

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Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities

Cited by 612 publications

References 154 publications

Computational Model Predicts Paracrine and Intracellular Drivers of Fibroblast Phenotype After Myocardial Infarction

Computational Model Predicts Paracrine and Intracellular Drivers of Fibroblast Phenotype After Myocardial Infarction

Lipopolysaccharide (LPS) induces increased epidermal green autofluorescence of mouse

Inflammatory cells and their non-coding RNAs as targets for treating myocardial infarction

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