[Drug therapies following heart failure and myocardial infarction(discussion)].
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Biomedical subjects
Publications and source records attributed to Issei Komuro.
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Pharmacological, device, and surgical therapies can be used in the management of heart failure. Because those conventional therapies are not effective in patients with the most severe heart failure, gene therapy is expected to become a viable alternative. The molecular pathways that contribute to the development of heart failure have been clarified in recent years. Specific molecular interventions have been evaluated in heart failure models, and the results indicate the potential for gene transfer strategies that are customized to target the individual molecular defects responsible for heart failure. Gene transfer studies have shown that modulating calcium homeostasis, manipulating beta-adrenergic receptor signaling, and augmenting cardiomyocyte resistance to apoptosis can be expected to be useful therapeutic modalities.
In cardiomyocytes, mechanical stress induces a variety of hypertrophic responses including an increase in protein synthesis and a reprogramming of gene expression. Recently, the calcium signaling has been reported to play an important role in the development of cardiac hypertrophy. In this article, we report on the role of the calcium signaling in stretch-induced gene expression in cardiomyocytes. Stretching of cultured cardiomyocytes up-regulates the expression of brain natriuretic peptide (BNP). Intracellular calcium-elevating agents such as the calcium ionophore A23187, the calcium channel agonist BayK8644 and the sarcoplasmic reticulum calcium-ATPase inhibitor thapsigargin up-regulate BNP gene expression. Conversely, stretch-induced BNP gene expression is suppressed by EGTA, stretch-activated ion channel inhibitors, voltage-dependent calcium channel antagonists, and long-time exposure to thapsigargin. Furthermore, stretch increases the activity of calcium-dependent effectors such as calcineurin and calmodulin-dependent kinase II, and inhibitors of calcineurin and calmodulin-dependent kinase II significantly attenuated stretch-induced hypertrophy and BNP expression. These results suggest that calcineurin and calmodulin-dependent kinase II are activated by calcium influx and subsequent calcium-induced calcium release, and play an important role in stretch-induced gene expression during the development of cardiac hypertrophy.
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Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to a nuclear receptor superfamily. PPARs have three isoforms: alpha, beta (or delta), and gamma. It is known that PPARgamma is expressed predominantly in adipose tissue and promotes adipocyte differentiation and glucose homeostasis. Recently, synthetic antidiabetic thiazolidinediones (TZDs) and the natural prostaglandin D2 (PGD2) metabolite, 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), have been identified as ligands for PPARgamma. Furthermore, it has become apparent that PPARs are present both in a variety of different cell types and in atherosclerotic lesions and the studies about PPARgamma have been extended. Although activation of PPARgamma appears to have protective effects on atherosclerosis, it is still largely uncertain whether PPARgamma ligands prevent the development of cardiovascular disease. Recent evidence suggests that some benefit from antidiabetic agents, TZDs, may occur independent of increased insulin sensitivity. In this article, we review the latest developments in the PPAR field and summarize the roles of PPARgamma and the actions of PPARgamma ligands in the cardiovascular system.
To analyze the kinesis and morphology of the acetabular labrum (AL) noninvasively, we applied 4-dimensional arthrography with motion-gated multislice computed tomography and compared the results with arthroscopy and Harris hip score (HHS) in 49 symptomatic patients who performed reciprocating hip flexion-extension as we carried out mimic retrospective electrocardiogram-gating acquisition. The kinematics and morphology of AL were classified as stabilized, irregular, or eccentric motion patterns. Of the 9 subjects who had intact or frayed AL on arthroscopy, 7 had stabilized motion (average 50 HHS) and 2 had irregular (44 HHS) motion by CT arthroscopy. Of the 16 without adhesive AL on arthroscopy, 6 had irregular motion (48 HHS) and 4 had eccentric motion (58 HHS). We found that the 4-dimensional arthrography with motion-gated multislice computed tomography can reveal both kinetic and morphological changes of the AL, and facilitate further stratification in subjects with the American Academy of Orthopaedic Surgeons class 0, or 1 or without "detached" morphological findings by arthroscopy.