FoxO3 normalizes Smad3-induced arterial smooth muscle cell growth.

Transition of arterial smooth muscle (ASM) from a quiescent, contractile state to a growth-promoting state is a hallmark of cardiovascular disease (CVD), a leading cause of death and disability in the United States and worldwide. While many individual signals have been identified as important mechanisms in this phenotypic conversion, the combined impact of the transcription factors Smad3 and FoxO3 in ASM growth is not known. The purpose of this study was to determine that a coordinated, phosphorylation-specific relationship exists between Smad3 and FoxO3 in the control of ASM cell growth. Using a rat in vivo arterial injury model and rat primary ASM cell lysates and fractions, validated low and high serum in vitro models of respective quiescent and growth states, and adenoviral (Ad-) gene delivery for overexpression (OE) of individual and combined Smad3 and/or FoxO3, we hypothesized that FoxO3 can moderate Smad3-induced ASM cell growth. Key findings revealed unique cellular distribution of Smad3 and FoxO3 under growth conditions, with induction of both nuclear and cytosolic Smad3 yet primarily cytosolic FoxO3; Ad-Smad3 OE leading to cytosolic and nuclear expression of phosphorylated and total Smad3, with almost complete reversal of each with Ad-FoxO3 co-infection in quiescent and growth conditions; Ad-FoxO3 OE leading to enhanced cytosolic expression of phosphorylated and total FoxO3, both reduced with Ad-Smad3 co-infection in quiescent and growth conditions; Ad-FoxO3 inducing expression and activity of the ubiquitin ligase MuRF-1, which was reversed with concomitant Ad-Smad3 OE; and combined Smad3/FoxO3 OE reversing both the pro-growth impact of singular Smad3 and the cytostatic impact of singular FoxO3. A primary takeaway from these observations is the capacity of FoxO3 to reverse growth-promoting effects of Smad3 in ASM cells. Additional findings lend support for reciprocal antagonism of Smad3 on FoxO3-induced cytostasis, and these effects are dependent upon discrete phosphorylation states and cellular localization and involve MuRF-1 in the control of ASM cell growth. Lastly, results showing capacity of FoxO3 to normalize Smad3-induced ASM cell growth largely support our hypothesis, and overall findings provide evidence for utility of Smad3 and/or FoxO3 as potential therapeutic targets against abnormal ASM growth in the context of CVD.

Orchestration of DNA Damage Checkpoint Dynamics across the Human Cell Cycle.

Although molecular mechanisms that prompt cell-cycle arrest in response to DNA damage have been elucidated, the systems-level properties of DNA damage checkpoints are not understood. Here, using time-lapse microscopy and simulations that model the cell cycle as a series of Poisson processes, we characterize DNA damage checkpoints in individual, asynchronously proliferating cells. We demonstrate that, within early G1 and G2, checkpoints are stringent: DNA damage triggers an abrupt, all-or-none cell-cycle arrest. The duration of this arrest correlates with the severity of DNA damage. After the cell passes commitment points within G1 and G2, checkpoint stringency is relaxed. By contrast, all of S phase is comparatively insensitive to DNA damage. This checkpoint is graded: instead of halting the cell cycle, increasing DNA damage leads to slower S phase progression. In sum, we show that a cell's response to DNA damage depends on its exact cell-cycle position and that checkpoints are phase-dependent, stringent or relaxed, and graded or all-or-none.

[Platelet antiaggregants or anticoagulants in the secondary prevention after myocardial infarct]. / Antiaggreganti piastrinici o anticoagulanti nella prevenzione secondaria dopo infarto miocardico.

Aspirin and oral anticoagulants are effective treatments in the secondary prevention after myocardial infarction. Aspirin at the dosage of 160-325 mg per day accomplishes a 21% reduction of the recurrences of vascular events (INR: 3-4). Oral anticoagulants are likely to be more effective; this therapy however is more demanding for the patient and the referring physician and is associated with a higher risk of hemorrhage. According to the available information from the literature, aspirin should be recommended for the majority of patients surviving after myocardial infarction. Oral anticoagulants should be reserved for post-infarction patients at high risk of thromboembolism and for those patients who present either intolerance to aspirin or recurrence of vascular events during aspirin treatment.

Cardiologic complications of subarachnoid hemorrhage.

Cardiac complications are frequent in patients with subarachnoid hemorrhage (SAH). They include ECG abnormalities, cardiac arrhythmias, myocardial damage, and neurogenic pulmonary edema. The pathophysiology of these abnormalities is related to an imbalance of the autonomic cardiovascular control and to increased circulating and local myocardial tissue catecholamines. Cardiac involvement is more common in patients with severe neurological deficits and it may increase the morbidity associated with SAH because of the occurrence of life-threatening arrhythmias or pulmonary edema. Monitoring of cardiac events in patients with SAH might result in a better understanding of their clinical outcome, as well as providing a basis for specific treatment capable of preventing myocardial necrosis and cardiac arrhythmias.

[Angioplasty in patients already treated with aortocoronary bypass: immediate and short-term results]. / L'angioplastica nei pazienti già operati di bypass aortocoronarico: risultati immediati e a breve termine.

Percutaneous transluminal coronary angioplasty (PTCA) is performed in patients with prior aortocoronary bypass grafting (CABG) with good results in native vessels and in the coronary graft anastomoses, but with high percentage of restenosis in the body and in the proximal portion of the grafts. The use of intracoronary stents is now spreading, their implantation can improve the immediate outcome and may decrease the incidence of restenosis, mostly in the body of the graft. In order to evaluate PTCA in CABG patients as to numbers and short-term results, the data regarding the year 1993 of 10 Italian Centers are presented. In these Centers 3,519 PTCA were performed, 233 (6.6%) of which on CABG patients. PTCA has been performed in native vessels in 136 patients and in CABG in 126 patients, with 29 patients treated in native vessels as well as in CABG. An angiographic and clinical success was obtained in 215 patients (92%). A major complication occurred in 11 (4.7%) patients with 8 (3.4%) myocardial infarctions, and 3 (1.3%) deaths. Forty-five (19.3%) stents were implanted with considerable differences among the Centers. One hundred seventy-three patients were followed up for 6 months: 110 (63.6%) were asymptomatic and 57 (32.9%) had complained angina; 27 (15.6%) had a second PTCA and 6 (3.5%) had CABG surgery; 1 patient (0.6%) suffered a myocardial infarction and 7 (4%) died (3 due to CABG reinterventions). To evaluate the long-term follow-up, data regarding 58 patients submitted to PTCA in the Institute of Cardiology of Bologna since 1985 to 1993 are showed, with a 3-year follow-up (36 +/- 26 months).(ABSTRACT TRUNCATED AT 250 WORDS)