Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heart remodeling is associated with the loss of cardiomyocytes and increase of fibrous tissue owing to abnormal mechanical load in a number of heart disease conditions. In present study, a well-described in vitro sustained stretch model was employed to study mechanical stretch-induced responses in both neonatal cardiomyocytes and cardiac fibroblasts. Cardiomyocytes, but not cardiac fibroblasts, underwent mitochondria-dependent apoptosis as evidenced by cytochrome c (cyto c) and Smac/DIABLO release from mitochondria into cytosol accompanied by mitochondrial membrane potential (Deltapsi(m)) reduction, indicative of mitochondrial permeability transition pore (PTP) opening. Cyclosporin A, an inhibitor of PTP, inhibited stretch-induced cyto c release, Deltapsi(m) reduction and apoptosis, suggesting an important role of mitochondrial PTP in stretch-induced apoptosis. The stretch also resulted in increased expression of the pro-apoptotic Bcl-2 family proteins, including Bax and Bad, in cardiomyocytes, but not in fibroblasts. Bax was accumulated in mitochondria following stretch. Cell permeable Bid-BH3 peptide could induce and facilitate stretch-induced apoptosis and Deltapsi(m) reduction in cardiomyocytes. These results suggest that Bcl-2 family proteins play an important role in coupling stretch signaling to mitochondrial death machinery, probably by targeting to PTP. Interestingly, the levels of p53 were increased at 12 h after stretch although we observed that Bax upregulation and apoptosis occurred as early as 1 h. Adenovirus delivered dominant negative p53 blocked Bax upregulation in cardiomyocytes but showed partial effect on preventing stretch-induced apoptosis, suggesting that p53 was only partially involved in mediating stretch-induced apoptosis. Furthermore, we showed that p21 was upregulated and cyclin B1 was downregulated only in cardiac fibroblasts, which may be associated with G2/M accumulation in response to mechanical stretch.
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PMID:Mechanical stretch induces mitochondria-dependent apoptosis in neonatal rat cardiomyocytes and G2/M accumulation in cardiac fibroblasts. 1504 Aug 86

Apoptosis a physiological mechanism that eliminates excessive, damaged or unwanted cells, is a highly regulated pathway important for maintaining homeostasis in multicellular organisms. It can be initiated through various signals via the extrinsic pathway which involves death receptors, or via the intrinsic pathway which is initiated by intracellular damage and involves the mitochondria and release of cytochrome c from it to further activate caspases. The Bcl-2 family of proteins is situated upstream to the irreversible damage of cellular constituents and is an important checkpoint in the fate of a cell. The pro-apoptotic members, BH3 only members include BID, BAD and BIM. They directly or indirectly activate multidomain BAX/BAK that constitute the requisite gateway to the intrinsic pathway which operates at the mitochondrial surface and endoplasmic reticulum. In contrast, antiapoptotic members such as Bcl-2, Bcl-XL bind and sequester activation. Downstream of mitochondria, the apoptosome involvement is seen to generate caspase activity. Post mitochondria regulation involves IAPs, and their inhibitors. The pathogenesis of several diseases such as cancer, neurodegenerative disorders, autoimmune disorders, heart disease, infectious diseases including AIDS is closely related to aberrant apoptosis. Consequently interest has emerged in employing various the rapeutic approaches such as gene therapy, antisense therapy, recombinant biologicals, organic and combinatorial chemistry, to specifically target apoptosis signaling pathways such as death receptors FAS/TRAIL, Bcl-2, p53, IAPs, SMAC and caspases, etc. and are now advancing from preclinical to clinical phase.
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PMID:Apoptosis in health and disease and modulation of apoptosis for therapy: An overview. 2310 76

Cancer and cardiovascular disease (CVD) have a common co-occurrence. Both diseases display overlapping pathophysiology and risk factors, suggesting shared biological mechanisms. Conditions such as obesity, diabetes, hypertension, smoking, poor diet, and inadequate physical activity can cause both heart disease and cancer. The burgeoning field of onco-cardiology aims to develop diagnostics and innovative therapeutics for both diseases through targeting shared mechanisms and molecular targets. In this overarching context, this expert review presents an analysis of the protein-protein interaction (PPI) networks for onco-cardiology drug discovery. Several PPI complexes such as MDM2-TP53 and CDK4-pRB have been studied for their tumor-suppressive functions. In addition, XIAP-SMAC, RAC1-GEF, Sur-2ESX, and TP53-BRCA1 are other PPI complexes that offer potential breakthrough for onco-cardiology therapeutics innovation. As both cancer and CVD share biological mechanisms to a certain degree, the PPI network analyses for onco-cardiology drug discovery are promising for addressing comorbid diseases in the spirit of systems medicine. We discuss the emerging architecture of PPI networks in cancer and CVD and prospects and challenges for their exploitation toward therapeutics applications. Finally, we emphasize that PPIs that were once thought to be undruggable have become potential new class of innovative drug targets.
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PMID:Discovering Innovative Drugs Targeting Both Cancer and Cardiovascular Disease by Shared Protein-Protein Interaction Network Analyses. 3132 50