Cardiovascular diseases are major increasing causes of death in developed countries. Coordinated transcriptional and post-transcriptional regulation of gene expression is crucial to maintain normal heart physiology. Dysregulation of these processes causes and/or accompanies multiple pathologies, such as cardiomyopathy and myocardial infarction. The exonuclease-mediated shortening of the mRNA poly(A) tail, a process called deadenylation, is a key step in regulated mRNA degradation, and deadenylation is mostly executed by the CCR4-NOT complex. CCR4-NOT complex is a multi-subunit protein complex, which controls gene expression in the levels from transcription through mRNA deadenylation and protein ubiquitination. We had previously identified CNOT3, a scaffold subunit of the CCR4-NOT complex, as a conserved regulator of heart function in Drosophila and mouse. Our recent genetic data of conditional Cnot3 knockout mice revealed unexpected association of poly(A) shortening and transcriptional activation, which is reprersented by Atg7 and p53. In this review, we introduce our recent progress in dissecting the mechanisms how poly(A) shortening contributes to controlling heart functions and overview new aspects of poly(A) regulation in maintaining cardiac homeostasis.

Autophagy is an evolutionarily conserved process for degradation of long-lived proteins and organelles that govern a number of cardiac pathologies which cause heart failure. Indeed, recent investigations have uncovered pathways that regulate autophagy in the heart and underlying mechanisms by which alterations in this process affect cardiac function and structure. One of the major roles of autophagy in cardiomyocytes is the intracellular protein quality control (PQC). Impairment of autophagy causes aggregation of damaged and/or misfolded proteins in cardiomyocytes, thereby damaging the cells which, in turn leads to pathological cardiac remodeling. We have shown previously that the molecular mechanism of autophagy suppression in response to cardiac stress. Activation of mammalian Ste20-like kinase 1 (Mst1) by stress causes autophagy suppression below physiological levels and inhibits PQC, which in turn contributes to cardiac dysfunction. Specifically, Mst1 inhibits autophagy through phosphorylation of Beclin1, enhancement of Beclin1-Bcl-2 interaction and suppression of Vps34. Here, I show recent advances in understanding the role of autophagy in pathological cardiac remodeling and discuss the therapeutic potential of modulating autophagy in heart disease.

Extracellular matrix (ECM) is a complex of non-cellular macromolecules which is indispensable not only for maintaining tissue structure but also for regulating the functions of surrounding cells via cell-ECM interaction. Recently, a number of ECM fragments termed “matricryptins” have been identified as novel endogenous bioactive substances, which usually have different bioactivity from that of original ECM. Because most matricryptins derived from basement membrane have anti-angiogenic and anti-tumor effects, they have been initially studied for developing anti-tumor agents. Meanwhile, there are several reports indicating that the expression of basement membrane-derived matricryptins changes in the heart tissue from experimental animal models as well as in the circulating blood from patients with cardiac diseases. Thus, it is logical to hypothesize that the basement membrane-derived matricryptins play roles in the development of cardiac diseases. In this article, we would like to introduce current findings on the functions of matricryptins including ours and discuss the possibility that they serve as a novel target for the treatment of heart failure.

Sepsis is the leading cause of death in critically ill patients, and its incidence continues to rise. Sepsis was defined as a systemic inflammatory response syndrome with an identifiable focus of infection, but therapeutic strategies aimed at eliminating the inflammatory response have only modest clinical benefit. The development of a failure of one or more organs poses a major threat to the survival of patients with sepsis, and mortality in sepsis is most often attributed to multiple organ dysfunction. Accordingly, sepsis has been recently redefined as life-threatening organ dysfunction due to a dysregulated host response to infection. Cardiac dysfunction is a well-recognized important component of septic multiple organ failure and can compromise the balance between oxygen supply and demand, ultimately leading to the development of multiple organ failure. The existence of cardiac dysfunction in sepsis is associated with much higher mortality when compared with septic patients without heart problems. Dobutamine, a β₁-selective adrenoceptor agonist, has been used in septic shock for many years as an only inotrope, but limited clinical outcome measures have been provided as to advisability of the usefulness of dobutamine in septic shock management. Here we provide an overview on the possible mechanisms underlying intrinsic myocardial depression during sepsis and discuss the perspective of several inotropes for sepsis-associated cardiac dysfunction.

SanBio Co., Ltd. is developing regenerative medicine, SB623. SB623 secretes neurotrophic and growth factors, and can possibly show benefit in repair of the damaged brain after stroke. An open-label, single-arm phase I/IIa clinical study was conducted with 18 chronic ischemic stroke patients in the United States to evaluate the safety and clinical outcomes of surgical transplantation of SB623. Clinical evaluation for a one year follow-up period showed significant improvements with all mean scores on the European Stroke Scale, the National Institute of Health Stroke Scale, and on the basis of fugl-Meyer Assessment. All patients experienced neither side effects nor serious treatment-emergent adverse events related to cell treatments. These results suggest that SB623 cell transplantation is safe and effective for treating chronic ischemic stroke. Currently we are conducting clinical studies in Japan and the US, and are accelerating clinical development to provide our cells to patients under new regulation of regenerative medical product in Japan.

Romidepsin (Brand name: ISTODAX_® for Injection 10 mg) is a novel antitumor drug that inhibits histone deacetylase (HDAC). Romidepsin strongly inhibited class I HDAC activity in vitro and demonstrated a strong antitumor activity against human tumor cell line xenograft in vivo. Based on its demonstrated efficacy against T-cell lymphoma in early clinical studies, multicenter phase II clinical studies in overseas with romidepsin were conducted in patients with cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), followed by approval for the treatment of CTCL and PTCL in the U.S. and other countries. Thereafter, domestic phase I/II studies were planned. The phase I study was designed to evaluate the tolerability of romidepsin in Japanese patients with relapsed or refractory PTCL/CTCL and thereby determine the recommended dose, as patients were administered romidepsin by intravenous infusion at a dose of 9 or 14 mg/m² over 4 hours on days 1, 8 and 15 of each 28-day cycle, and 14 mg/m² was determined as the recommended dose for phase II. While the phase II study was designed to include 40 Japanese patients with relapsed or refractory PTCL to evaluate the efficacy and safety of romidepsin. Treatment response was 42.5% and the most common AEs of Grade ≥ 3 were lymphopenia (74.0%), neutropenia (54.0%), leukocytopenia (46.0%) and thrombocytopenia (38.0%). The overall safety profile was considered to be within the acceptable range. On the basis of these result, romidepsin was approved in July 2017 for the treatment of relapsed or refractory PTCL in Japan.