NEWS, ARTICLES AND PRESS RELEASES
May 17, 2017: Research Article
BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure
Abstract: 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.
May 17, 2017: Press Release
Cancer-Cardiac Connection Illuminates Promising New Drug for Heart Failure
A team of researchers at the Gladstone Institutes uncovered a new strategy to treat heart failure, a leading contributor to mortality and healthcare costs in the United States. Despite widespread use of currently-approved drugs, approximately 40% of patients with heart failure die within 5 years of their initial diagnosis.
February 8, 2017: Gladstone News
Healing Hearts Across the Lifespan
From grandparents to grandchildren, patients with heart disease will benefit from cardiovascular research at the Gladstone Institutes. A trio of Gladstone scientists are studying the basic biology of the heart to guide the discovery of new therapies for conditions such as congenital heart disease and heart failure.
December 6, 2016: Press Release
Tenaya Therapeutics Launches with the Goal of Curing Heart Disease
A new biopharmaceutical company, Tenaya Therapeutics Inc., will build on discoveries in cardiovascular disease research made at the Gladstone Institutes, concentrating on regenerative medicine and drug discovery for heart failure. The new company combines Gladstone’s basic science expertise with the resources and translational know-how of the biotechnology industry.
August 18, 2016: News Article
Cancer Drug Offers Hope to Treat Heart Failure
Taking inspiration from cancer research, Gladstone associate investigator and adult cardiologist Saptarsi Haldar, MD, investigates how to fix harmful gene expression in damaged heart cells.
For people with heart failure, the prospects for a long and active life are limited. Most will be unable to jog or climb stairs without getting dangerously short of breath or even risking sudden death. Current drugs work at the surface of heart muscle cells to block stress hormones, such as adrenaline, that are produced when the heart is injured. However, despite widespread use of these therapies, a staggering 40 percent of heart failure patients will die within 5 years of diagnosis.
Fortunately, there is new hope in the fight against heart failure. Taking unexpected inspiration from cancer research, Gladstone’s newest associate investigator, adult cardiologist Saptarsi Haldar, MD, studies a class of drugs that may treat heart failure closer to the source of the problem.
July 14, 2016: Research Article
Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA
Summary: BRD4 governs pathological cardiac gene expression by binding acetylated chromatin, resulting in enhanced RNA polymerase II (Pol II) phosphorylation and transcription elongation. Here, we describe a signal-dependent mechanism for the regulation of BRD4 in cardiomyocytes. BRD4 expression is suppressed by microRNA-9 (miR-9), which targets the 3′ UTR of the Brd4 transcript. In response to stress stimuli, miR-9 is downregulated, leading to derepression of BRD4 and enrichment of BRD4 at long-range super-enhancers (SEs) associated with pathological cardiac genes. A miR-9 mimic represses stimulus-dependent targeting of BRD4 to SEs and blunts Pol II phosphorylation at proximal transcription start sites, without affecting BRD4 binding to SEs that control constitutively expressed cardiac genes. These findings suggest that dynamic enrichment of BRD4 at SEs genome-wide serves a crucial role in the control of stress-induced cardiac gene expression and define a miR-dependent signaling mechanism for the regulation of chromatin state and Pol II phosphorylation.
May 26, 2016: Review Article
Sarcomeres and Cardiac Growth: Tension in the Relationship
Abstract: Genetic mutations in the cardiomyocyte contractile apparatus cause aberrant cardiac growth categorized morphologically as hypertrophic or dilated. A recent study leverages an array of mutant mouse models to extrapolate a new integrated parameter: the myofilament 'tension index', which predicts patterns of cardiac growth resulting from individual sarcomeric mutations. These findings may inform genotype-specific therapies.
December 8, 2015: Research Article
Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program
Abstract: Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC–KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming.
November 23, 2015: Press Release
Gene Identified that Produces the Benefits of Steroids, but Without the Detrimental Side Effects
Scientists have revealed that glucocorticoids, a class of steroid hormones that are commonly prescribed as drugs, enhance muscle endurance and alleviate muscular dystrophy through activation of the gene KLF15. Critically, this pathway is not involved in muscle wasting or the other major detrimental effects of prolonged steroid use. The discovery, published in The Proceedings of the National Academy of Sciences, could lead to the development of new medications that improve muscle function without the negative consequences caused by long-term steroid exposure. This advance is especially important for progressive muscle wasting diseases like Duchenne’s muscular dystrophy (DMD).
August 7, 2013: News
Researchers discover new designer compound that treats heart failure
Researchers from Case Western Reserve University School of Medicine and the Dana-Farber Cancer Institute have made a fundamental discovery relevant to the understanding and treatment of heart failure, a leading cause of death worldwide. The team discovered a new molecular pathway responsible for causing heart failure and showed that a first-in-class prototype drug, JQ1, blocks this pathway to protect the heart from damage.
August 5, 2013: News
Cleveland Cardiologist Discovers Possible New Heart Failure Therapy
A new study released in the peer-reviewed journal Cell highlights a discovery that could change the way heart failure is treated. The work was done by a young cardiologist who saw patients returning too many times to the intensive care unit at University Hospitals. Ideastream's Sarah Jane Tribble explains the research and its possible impact.
August 1, 2013: Press Release
New Target in Heart Failure
Researchers from Harvard Medical School, Dana-Farber Cancer Institute and Case Western Reserve University School of Medicine have made a fundamental discovery relevant to the understanding and treatment of heart failure, a leading cause of death worldwide. The team discovered a new molecular pathway responsible for causing heart failure and showed that a first-in-class prototype drug, JQ1, blocks this pathway to protect the heart from damage.