Therapeutic Regulation of Cardiac Fibroblast Function: Targeting stress-activated Protein Kinase Pathways

Turner, Neil A.

doi:10.2217/fca.11.41

Cited by 22 publications

(28 citation statements)

References 118 publications

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“…We hypothesize that miR-21 exerts its influence on the activation of heat stress response cascades via Taf7, which has been shown to interact with HSF-activation complexes (Yuan and Gurley 2000). Additionally, Taf7 may act as a node for miR-21's integration into additional stress response pathways, as increasing amounts of Taf7 in HEK293 and COS cells correlate with enhanced transactivation of c-Jun, an AP-1 transcription factor activated by stress-activated protein kinases (SAPKs) (Munz et al 2003;Mehan et al 2011;Turner 2011). In the future, it will be important to further test for links between miR-21 and stress to determine which stresses and stress-related pathways miR-21 may respond to in various tissues.…”

Section: Mir-21 Regulation Is Specifically Linked To Stress Response mentioning

confidence: 99%

Disease-linked microRNA-21 exhibits drastically reduced mRNA binding and silencing activity in healthy mouse liver

Androsavich¹,

Chau²,

Bhat³

et al. 2012

RNA

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MicroRNAs (miRNAs) bind to mRNAs and fine-tune protein output by affecting mRNA stability and/or translation. miR-21 is a ubiquitous, highly abundant, and stress-responsive miRNA linked to several diseases, including cancer, fibrosis, and inflammation. Although the RNA silencing activity of miR-21 in diseased cells has been well documented, the roles of miR-21 under healthy cellular conditions are not well understood. Here, we show that pharmacological inhibition or genetic deletion of miR-21 in healthy mouse liver has little impact on regulation of canonical seed-matched mRNAs and only a limited number of genes enriched in stress response pathways. These surprisingly weak and selective regulatory effects on known and predicted target mRNAs contrast with those of other abundant liver miRNAs such as miR-122 and let-7. Moreover, miR-21 shows greatly reduced binding to polysome-associated target mRNAs compared to miR-122 and let-7. Bioinformatic analysis suggests that reduced thermodynamic stability of seed pairing and target binding may contribute to this deficiency of miR-21. Significantly, these trends are reversed in human cervical carcinoma (HeLa) cells, where miRNAs including miR-21 show enhanced target binding within polysomes and where miR-21 triggers strong degradative activity toward target mRNAs. Taken together, our results suggest that, under normal cellular conditions in liver, miR-21 activity is maintained below a threshold required for binding and silencing most of its targets. Consequently, enhanced association with polysome-associated mRNA is likely to explain in part the gain of miR-21 function often found in diseased or stressed cells.

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Section: Mir-21 Regulation Is Specifically Linked To Stress Response mentioning

confidence: 99%

Disease-linked microRNA-21 exhibits drastically reduced mRNA binding and silencing activity in healthy mouse liver

Androsavich¹,

Chau²,

Bhat³

et al. 2012

RNA

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“…Cardiac fibroblasts, including the active collagen-secreting myofibroblasts, are the dominant cell type in the infarct region and are recognized as essential in infarct remodeling [7, 20, 41, 43]. Myofibroblasts typically appear in the infarct area at 4–5 days after AMI, reach a peak at 1–2 weeks and continue to reside up to at least 4 weeks [10] and possibly months to years [43].…”

Section: Discussionmentioning

confidence: 99%

Intermittent pacing therapy favorably modulates infarct remodeling

et al. 2017

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Despite early revascularization, remodeling and dysfunction of the left ventricle (LV) after acute myocardial infarction (AMI) remain important therapeutic targets. Intermittent pacing therapy (IPT) of the LV can limit infarct size, when applied during early reperfusion. However, the effects of IPT on post-AMI LV remodeling and infarct healing are unknown. We therefore investigated the effects of IPT on global LV remodeling and infarct geometry in swine with a 3-day old AMI. For this purpose, fifteen pigs underwent 2 h ligation of the left circumflex coronary artery followed by reperfusion. An epicardial pacing lead was implanted in the peri-infarct zone. After three days, global LV remodeling and infarct geometry were assessed using magnetic resonance imaging (MRI). Animals were stratified into MI control and IPT groups. Thirty-five days post-AMI, follow-up MRI was obtained and myofibroblast content, markers of extracellular matrix (ECM) turnover and Wnt/frizzled signaling in infarct and non-infarct control tissue were studied. Results showed that IPT had no significant effect on global LV remodeling, function or infarct mass, but modulated infarct healing. In MI control pigs, infarct mass reduction was principally due to a 26.2 ± 4.4% reduction in infarct thickness (P ≤ 0.05), whereas in IPT pigs it was mainly due to a 35.7 ± 4.5% decrease in the number of infarct segments (P ≤ 0.05), with no significant change in infarct thickness. Myofibroblast content of the infarct zone was higher in IPT (10.9 ± 2.1%) compared to MI control (5.4 ± 1.6%; P ≤ 0.05). Higher myofibroblast presence did not coincide with alterations in expression of genes involved in ECM turnover or Wnt/frizzled signaling at 5 weeks follow-up. Taken together, IPT limited infarct expansion and altered infarct composition, showing that IPT influences remodeling of the infarct zone, likely by increasing regional myofibroblast content.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-017-0616-3) contains supplementary material, which is available to authorized users.

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“…All of these pathways have also been shown to be activated in the myocardium early after experimental MI; see recent comprehensive reviews on NF-κB (Gordon et al, 2011), p38 (Marber et al, 2011;Turner, 2011), JNK (Turner, 2011), ERK and Akt; the latter being components of the reperfusion injury salvage kinase (RISK) pathway that is considered cardioprotective (Hausenloy et al, 2005). However, these studies do not shed particular light on IL-1 signalling in CF due to the heterogeneity of cell types in the 16 heart and the multitude of potential stimuli for these pathways after MI (in addition to IL-1).…”

Section: Il-1 Signalling In Cfmentioning

confidence: 99%

“…The p38 MAPK pathway plays an important role in regulating various aspects of the myocardial remodelling process, including CF function (Marber et al, 2011;Turner, 2011).…”

Section: Il-1 Signalling In Cfmentioning

confidence: 99%

Effects of interleukin-1 on cardiac fibroblast function: Relevance to post-myocardial infarction remodelling

Turner

2014

Vascular Pharmacology

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The cardiac fibroblast (CF) is a multifunctional and heterogeneous cell type that plays an essential role in regulating cardiac development, structure and function. Following myocardial infarction (MI), the myocardium undergoes complex structural remodelling in an attempt to repair the damaged tissue and overcome the loss of function induced by ischemia/reperfusion injury. Evidence is emerging that CF play critical roles in all stages of post-MI remodelling, including the initial inflammatory phase that is triggered in response to myocardial damage. CF are particularly responsive to the proinflammatory cytokine interleukin-1 (IL-1) whose levels are rapidly induced in the myocardium after MI. Studies from our laboratory in recent years have sought to evaluate the functional effects of IL-1 on human CF function and to determine the underlying molecular mechanisms. This review summarises these data and sets it in the context of post-MI cardiac remodelling, identifying the fibroblast as a potential therapeutic target for reducing adverse cardiac remodelling and its devastating consequences.3

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Therapeutic Regulation of Cardiac Fibroblast Function: Targeting stress-activated Protein Kinase Pathways

Cited by 22 publications

References 118 publications

Disease-linked microRNA-21 exhibits drastically reduced mRNA binding and silencing activity in healthy mouse liver

Disease-linked microRNA-21 exhibits drastically reduced mRNA binding and silencing activity in healthy mouse liver

Intermittent pacing therapy favorably modulates infarct remodeling

Effects of interleukin-1 on cardiac fibroblast function: Relevance to post-myocardial infarction remodelling

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