MMI-0100 inhibits cardiac fibrosis in myocardial infarction by direct actions on cardiomyocytes and fibroblasts via MK2 inhibition

Xu, Lei; Yates, Cecelia C.; Lockyer, Pamela; Xie, Liang; Bevilacqua, Ariana; He, Jun; Lander, Cynthia; Patterson, W. Cam; Willis, Monte S.

doi:10.1016/j.yjmcc.2014.09.011

Cited by 39 publications

(43 citation statements)

References 77 publications

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“…We initially dosed at 25 mg/kg daily for 6 days (during the period of early surgical recovery) and subsequently ramped up to 50 mg/kg daily until postoperative day 28 (a time point when robust pathologic remodeling of the remote LV myocardium is present in this model) (protocol in Fig. 2A) (35). Similar to our findings in the pressure overload treatment model (Fig.…”

Section: Resultsmentioning

confidence: 99%

BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure

et al. 2017

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Despite current standard of care, the average 5-year mortality after an initial diagnosis of heart failure (HF) is about 40%, reflecting an urgent need for new therapeutic approaches. Previous studies demonstrated that the epigenetic reader protein bromodomain-containing protein 4 (BRD4), an emerging therapeutic target in cancer, functions as a critical coactivator of pathologic gene transactivation during cardiomyocyte hypertrophy. However, the therapeutic relevance of these findings to human disease remained unknown. We demonstrate that treatment with the BET bromodomain inhibitor JQ1 has therapeutic effects during severe, preestablished HF from prolonged pressure overload, as well as after a massive anterior myocardial infarction in mice. Furthermore, JQ1 potently blocks agonist-induced hypertrophy in human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). Integrated transcriptomic analyses across animal models and human iPSC-CMs reveal that BET inhibition preferentially blocks transactivation of a common pathologic gene regulatory program that is robustly enriched for NFκB and TGF-β signaling networks, typified by innate inflammatory and profibrotic myocardial genes. As predicted by these specific transcriptional mechanisms, we found that JQ1 does not suppress physiological cardiac hypertrophy in a mouse swimming model. These findings establish that pharmacologically targeting innate inflammatory and profibrotic myocardial signaling networks at the level of chromatin is effective in animal models and human cardiomyocytes, providing the critical rationale for further development of BET inhibitors and other epigenomic medicines for HF.

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Section: Resultsmentioning

confidence: 99%

BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure

et al. 2017

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“…Cultured fibroblasts treated with AngII showed that p38 activation was necessary for fibrosis while TGFβ prolonged p38-dependent increases in the expression of matrix proteins like collagen and fibronectin, as well as αSMA 11, 41, 42 . Our in vitro assays place p38 downstream of extracellular signals like TGFβ, AngII, but upstream of known myofibroblast regulatory factors such as calcineurin, TRPC6, MK2, and SRF 11, 21, 39, 40 . The temporal, lineage, and injury dependent activation of these combined molecular regulators will thus ultimately determine fibroblast function and hence the degree of fibrosis and its temporal persistence.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast-Specific Genetic Manipulation of p38 Mitogen-Activated Protein Kinase In Vivo Reveals Its Central Regulatory Role in Fibrosis

et al. 2017

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Background In the heart acute injury induces a fibrotic healing response that generates collagen rich scarring that is at first protective but if inappropriately sustained can worsen heart disease. The fibrotic process is initiated by cytokines, neuroendocrine effectors and mechanical strain that promote resident fibroblast differentiation into contractile and extracellular matrix producing myofibroblasts. The mitogen-activated protein kinase (MAPK) p38α (Mapk14 gene) is known to influence the cardiac injury response, but its direct role in orchestrating programmed fibroblast differentiation and fibrosis in vivo is unknown. Methods A conditional Mapk14 allele was used to delete the p38α encoding gene specifically in cardiac fibroblasts or myofibroblasts using 2 different tamoxifen-inducible Cre recombinase expressing gene-targeted mouse lines. Mice were subjected to ischemic injury or chronic neurohumoral stimulation and monitored for survival, cardiac function and fibrotic remodeling. Antithetically, mice with fibroblast-specific transgenic overexpression of activated MAPK kinase 6 (MKK6), a direct inducer of p38, were generated to investigate if this pathway can directly drive myofibroblast formation and the cardiac fibrotic response. Results In mice loss of Mapk14 blocked cardiac fibroblast differentiation into myofibroblasts and ensuing fibrosis in response to ischemic injury or chronic neurohumoral stimulation. A similar inhibition of myofibroblast formation and healing was also observed in a dermal wounding model with deletion of Mapk14. Transgenic mice with fibroblast-specific activation of MKK6-p38 developed interstitial and perivascular fibrosis in the heart, lung and kidney due to enhanced myofibroblast numbers. Mechanistic experiments show that p38 transduces cytokine and mechanical signals into myofibroblast differentiation through the transcription factor serum-response factor (SRF) and the signaling effector calcineurin. Conclusions These findings suggest that signals from diverse modes of injury converge on p38α MAPK within the fibroblast to program the fibrotic response and myofibroblast formation in vivo, suggesting a novel therapeutic approach with p38 inhibitors for future clinical application.

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“…Slides were scanned using an Aperio ScanScope (Aperio Technologies, Vista, CA) and fibrosis was quantified using Aperio ImageScope (v12.3.2.8013). The Positive Pixel Count v9 algorithm was used to measure staining of collagen (representing both fibrosis and collagen in extracellular matrix [ECM]), with hue value and width of 0.66 and 0.1, respectively 29. The N positive/N total value representing the percentage of collagen of the entire section was used to determine the weighted average for each slide, expressed as percentage of fibrosis.…”

Section: Methodsmentioning

confidence: 99%

Modeling the Transition From Decompensated to Pathological Hypertrophy

Pascual

Schisler

Grevengoed

et al. 2018

JAHA

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BackgroundLong‐chain acyl‐CoA synthetases (ACSL) catalyze the conversion of long‐chain fatty acids to fatty acyl‐CoAs. Cardiac‐specific ACSL1 temporal knockout at 2 months results in a shift from FA oxidation toward glycolysis that promotes mTORC1‐mediated ventricular hypertrophy. We used unbiased metabolomics and gene expression analyses to examine the early effects of genetic inactivation of fatty acid oxidation on cardiac metabolism, hypertrophy development, and function.Methods and ResultsGlobal cardiac transcriptional analysis revealed differential expression of genes involved in cardiac metabolism, fibrosis, and hypertrophy development in Acsl1 H−/− hearts 2 weeks after Acsl1 ablation. Comparison of the 2‐ and 10‐week transcriptional responses uncovered 137 genes whose expression was uniquely changed upon knockdown of cardiac ACSL1, including the distinct upregulation of fibrosis genes, a phenomenon not observed after complete ACSL1 knockout. Metabolomic analysis identified metabolites altered in hearts displaying partially reduced ACSL activity, and rapamycin treatment normalized the cardiac metabolomic fingerprint.ConclusionsShort‐term cardiac‐specific ACSL1 inactivation resulted in metabolic and transcriptional derangements distinct from those observed upon complete ACSL1 knockout, suggesting heart‐specific mTOR (mechanistic target of rapamycin) signaling that occurs during the early stages of substrate switching. The hypertrophy observed with partial Acsl1 ablation occurs in the context of normal cardiac function and is reminiscent of a physiological process, making this a useful model to study the transition from physiological to pathological hypertrophy.

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MMI-0100 inhibits cardiac fibrosis in myocardial infarction by direct actions on cardiomyocytes and fibroblasts via MK2 inhibition

Cited by 39 publications

References 77 publications

BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure

BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure

Fibroblast-Specific Genetic Manipulation of p38 Mitogen-Activated Protein Kinase In Vivo Reveals Its Central Regulatory Role in Fibrosis

Modeling the Transition From Decompensated to Pathological Hypertrophy

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