Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Restenosis after angioplasty is one of the most critical problems of the various interventional therapies for myocardial ischemia. It has been difficult to prevent the vascular smooth muscle cells (VSMCs) proliferation resulting in restenosis. The goal of this study was to prove the treatment by hyperthermia to be effective in suppressing VSMC's proliferation in vitro. When just-stimulated VSMCs, which were incubated for 2h after 5% FBS stimulation to quiescent VSMCs, were exposed to hyperthermia (43 degrees C, 2h), the cell cycle progression to S and G2/M phase was significantly delayed 24h after 5% FBS stimulation. And another 24h later, cell death was observed partly (19%) of heat-treated VSMCs. Nonetheless, hyperthermia under the same conditions did not result in the death of quiescent VSMCs, and did not inhibit the proliferation of cultured bovine aortic endothelial cells (BAECs). In addition, we found that hyperthermia (43 degrees C, 2h) elevated p27(Kip1) over the amount induced in confluent VSMCs. Much elevation of p27(Kip1), which is a negative regulator of G1/S progression, may play a role in heat-induced G1 arrest of VSMCs. In conclusion, we have found that hyperthermia (43 degrees C, 2h) inhibited the proliferation of the dividing VSMCs mainly due to G1 arrest with neither inhibiting the generation of BAECs nor damaging quiescent VSMCs. Hence, our data suggest that hyperthermia may be clinically applicable for the prevention of restenosis.
 ...
PMID:Hyperthermia at 43 degrees C for 2h inhibits the proliferation of vascular smooth muscle cells, but not endothelial cells. 1239 94

Nitric oxide (NO) has been shown to play a key role in the regulation of cardiac hypertrophy and fibrosis in response to myocardial ischemia in part by antagonizing the action of angiotensin II (Ang II). In this study, we investigated the potential protective role of human endothelial nitric oxide synthase (eNOS) in left ventricular (LV) remodeling after myocardial infarction (MI) by a somatic gene transfer approach. Male Wistar rats underwent coronary artery ligation to induce MI. One week after surgery, adenovirus encoding the human eNOS or luciferase gene under the control of the CMV promoter/enhancer was injected into rats via the tail vein, and animals were sacrificed at 1 and 5 weeks after gene transfer. Successful gene transfer was evaluated based on increased levels of NO and cGMP in the heart, measured at one week after eNOS gene delivery. Six weeks after MI, the LV end-diastolic pressure, heart weight, LV axis length and cardiomyocyte size were markedly increased compared to the Sham group, while eNOS gene delivery significantly reduced these parameters. Rats receiving control virus developed considerably more fibrotic lesions identified by Sirius Red staining and collagen I immunostaining compared to Sham rats, and eNOS gene delivery significantly reduced collagen accumulation. eNOS gene transfer also reduced TUNEL-positive apoptotic cells. The cardioprotective effect of NO was accompanied by reduced NADH and NADPH oxidase activities and superoxide formation, TGF-beta1 and p27 levels, JNK activation, NF-kappa B nuclear translocation, and caspase-3 activity. This study shows that NO may play an important role in attenuating cardiac remodeling and apoptosis after myocardial infarction via suppression of oxidative stress-mediated signaling pathways.
 ...
PMID:Human endothelial nitric oxide synthase gene delivery protects against cardiac remodeling and reduces oxidative stress after myocardial infarction. 1576 77

Cardiac fibroblast hyperplasia associated with augmented matrix production is central to wound healing following myocardial injury. Regulation of the cardiac fibroblast cell cycle by factors in the diseased myocardium that can potentially modify the hyperplastic response of cardiac fibroblasts has, however, not been investigated. We examined the regulation of the cardiac fibroblast cell cycle by hypoxia, a major constituent of myocardial ischemia. Significant reductions in DNA synthesis and cell number, and flow cytometry indicated decreased G1/S progression in hypoxic adult rat cardiac fibroblasts. Western blot analysis showed reduced levels of cyclin D and cyclin A, induction of p27 and hypophosphorylation of Rb under hypoxia. Skp2, which targets p27 for degradation, was significantly lower and inversely related to p27 protein levels in hypoxic cells. Marked p38 MAPK activation was observed under hypoxia and its inhibition using SB203580 reversed the effects of hypoxia on DNA synthesis, cell cycle phase distribution, p27, and cyclin D1 but not cyclin A. Interestingly, a 2-fold increase in p27 mRNA in hypoxic cells, demonstrated by real-time PCR, was unaffected by SB203580, which, however, reversed the hypoxic inhibition of Skp2. In summary, p38 MAPK is an important determinant of hypoxia-induced G0/G1 block in cardiac fibroblasts. p27 induction in hypoxic cardiac fibroblasts may involve direct transcriptional regulation, independent of p38 MAPK, and post-translational regulation via p38 MAPK-dependent suppression of its degradation by Skp2. The study identifies Skp2 as a potential downstream target of p38 MAPK, suggesting a novel mechanism of G1-S regulation in cardiac fibroblasts exposed to stress conditions.
 ...
PMID:p38 MAPK regulates G1-S transition in hypoxic cardiac fibroblasts. 2142 May 5

A number of recent studies have suggested that cardiac myocytes, previously considered post-mitotic, re-enter the cell cycle and possess the ability to proliferate with certain pathogenic stimuli. To study this further, we examined cellular proliferation in myocardial tissue from subjects with chronic ischemic heart disease-associated myocardial infarction and subsequent congestive heart failure. We found striking increases in cytoplasmic phospho-p27, a well-known mitotic regulator, compared to controls by both immunocytochemical and immunoblot analyses. However, we found no evidence for cardiac myocyte proliferation in either disease or control subjects using both mitotic counting (no mitotic figures were observed) and Ki-67 immunocytochemistry, which demonstrated a 0% proliferation index. That increased cytoplasmic phospho-p27 is not accompanied by division prompts us to speculate that ectopic cell cycle activation occurs in the face of minimal to absent myocyte proliferation per se. Based on these findings, and the parallel findings in post-mitotic neurons in neurodegenerative disease, we suggest that cell-cycle activation in ischemic heart disease is a deleterious event that perpetuates disease pathogenesis culminating in myocardial failure.
 ...
PMID:Sequestration of p27 within the cytoplasm of cardiac myocytes in chronic ischemic heart disease: pathogenic implications for ischemic cardiomyopathy. 2359 81

FoxO3a, a member of the forkhead transcription factors, has been demonstrated to be involved in myocardial ischemia/reperfusion (I/R) injury. Cardiac microvascular endothelial cells (CMECs) are some of the predominant cells damaged immediately after myocardial I/R injury. Despite the importance of injured CMECs in an ischemic heart, little is known about the involvement of FoxO3a in regulating CMECs injury. Thus, we used rat CMECs following simulated I/R to examine FoxO3a activation and signaling in relation to survival, the cell cycle and apoptosis in CMECs. We found that Akt negatively regulates activation of the FoxO3a pathway by phosphorylating FoxO3a in CMECs as demonstrated with an Akt inhibitor and activator. Upon I/R injury, the FoxO3a pathway was significantly activated in CMECs, which was accompanied by Akt deactivation. In parallel, the I/R of CMECs induced G1-phase arrest through p27(Kip1) up-regulation and significant activation of caspase-3. Accordingly, inhibition of the FoxO3a pathway by IGF-1, an Akt activator, could significantly block the I/R-enhanced activation of p27(Kip1) and caspase-3 in CMECs. Collectively, our results indicate that the FoxO3a pathway is involved in the I/R injury of CMECs at least in part through the regulation of cell cycle arrest and apoptosis, suggesting that the FoxO3a pathway may be a novel therapeutic target that protects against microvascular endothelial damage in ischemic hearts.
 ...
PMID:Involvement of the FoxO3a pathway in the ischemia/reperfusion injury of cardiac microvascular endothelial cells. 2394 78

p27(Kip1) (p27), a key regulator of cell division, has been implicated in autophagy of cancer cells. However, its role in autophagy, the evolutionarily conserved catabolic process that enables cells to remove unwanted proteins and damaged organelles, had not been examined in the heart. Here we report that ectopic delivery of a p27 fusion protein (TAT-p27) was sufficient to induce autophagy in neonatal rat ventricular cardiomyocytes in vitro, under basal conditions and after glucose deprivation. Conversely, lentivirus-delivered shRNA against p27 successfully reduced p27 levels and suppressed basal and glucose-deprived levels of autophagy in cardiomyocytes in vitro. Glucose deprivation mimics myocardial ischemia and induces apoptosis in cardiomyocytes. During glucose deprivation, TAT-p27 inhibited apoptosis, whereas down-regulation of p27 decreased survival of cardiomyocytes. However, inhibition of autophagy by pharmacological (3-methyladenine, chloroquine, or bafilomycin A1) or genetic approaches (siRNA-mediated knockdown of Atg5) sensitized cardiomyocytes to glucose deprivation-induced apoptosis, even in the presence of TAT-p27. TAT-p27 was also able to provoke greater levels of autophagy in resting and fasting cardiomyocytes in vivo. Further, TAT-p27 enhanced autophagy and repressed cardiomyocytes apoptosis, improved cardiac function, and reduced infarct size following myocardial infarction. Again, these effects were lost when cardiac autophagy in vivo was blocked by chloroquine. Taken together, these data show that p27 positively regulates cardiac autophagy in vitro and in vivo, at rest and after metabolic stress, and that TAT-p27 inhibits apoptosis by promoting autophagy in glucose-deprived cardiomyocytes in vitro and in post-myocardial infarction hearts in vivo.
...
PMID:p27 protein protects metabolically stressed cardiomyocytes from apoptosis by promoting autophagy. 2479 71

Myocardial ischemia/reperfusion injury (MIRI) is a clinically familiar disease, which possesses a great negative impact on human health. But, the effective treatment is still absent. MicroRNAs (miRNAs) have been testified to play a momentous role in MIRI. The purpose of the study aimed to probe the functions of miR-132 in oxygen and glucose deprivation (OGD)-evoked injury in H9c2 cells. miR-132 expression in H9c2 cells accompanied by OGD disposition was evaluated via real-time quantitative polymerase chain reaction. After miR-132 mimic and inhibitor transfections, the impacts of miR-132 on OGD-affected H9c2 cell viability, apoptosis, cell cycle, and the interrelated factors were appraised by exploiting cell counting kit-8, flow cytometry, and western blot analysis. FOXO3A expression was estimated in above-transfected cells, meanwhile, the correlation between miR-132 and FOXO3A was probed by dual-luciferase report assay. Ultimately, above mentioned cell processes were reassessed in H9c2 cells after preprocessing OGD administration and transfection with si-FOXO3A and si-NC plasmids. We got that OGD disposition obviously enhanced miR-132 expression in H9c2 cells. Overexpressed miR-132 evidently reversed OGD-evoked cell viability repression and apoptosis induction in H9c2 cells. In addition, overexpressed miR-132 mitigated OGD-evoked G0/G1 cell arrest by mediating p21, p27, and cyclin D1 expression. Repression of FOXO3A was observed in miR-132 mimic-transfected cells, which was also predicated as a direct gene of miR-132. We discovered that silenced FOXO3A alleviated OGD-evoked cell injury in H9c2 cells via facilitating cell viability, hindering apoptosis and restraining cell arrest at G0/G1 phase. In conclusion, these investigations corroborated that miR-132 exhibited the protective impacts on H9c2 cells against OGD-evoked injury via targeting FOXO3A.
 ...
PMID:MicroRNA-132 protects H9c2 cells against oxygen and glucose deprivation-evoked injury by targeting FOXO3A. 3121 Mar 52