The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma.

Intrinsic and acquired chemoresistance are frequent causes of cancer eradication failure. Thus, long-term cis-diaminedichloroplatine(II) (CDDP) or cisplatin treatment is known to promote tumor cell resistance to apoptosis induction via multiple mechanisms involving gene expression modulation of oncogenes, tumor suppressors and blockade of pro-apoptotic mitochondrial membrane permeabilization. Here, we demonstrate that CDDP-resistant non-small lung cancer cells undergo profound remodeling of their endoplasmic reticulum (ER) proteome (>80 proteins identified by proteomics) and exhibit a dramatic overexpression of two protein disulfide isomerases, PDIA4 and PDIA6, without any alteration in ER-cytosol Ca(2+) fluxes. Using pharmacological and genetic inhibition, we show that inactivation of both proteins directly stimulates CDDP-induced cell death by different cellular signaling pathways. PDIA4 inactivation restores a classical mitochondrial apoptosis pathway, while knockdown of PDIA6 favors a non-canonical cell death pathway sharing some necroptosis features. Overexpression of both proteins has also been found in lung adenocarcinoma patients, suggesting a clinical importance of these proteins in chemoresistance.

Anti-ischemic effects of angiotensin-converting enzyme inhibitors: a future therapeutic perspective.

The renin-angiotensin system and angiotensin-converting enzyme (ACE) are increasingly being implicated in the pathogenesis of coronary artery disease and its sequelae and the potential of ACE inhibitors to protect the heart is a topic that has emerged recently as a matter for scientific discussion. Experimental and clinical studies have shown the beneficial effects of ACE inhibitors on the metabolism, function and structure of healthy and damaged hearts and these data support the concept of both primary and secondary cardioprotection with this class of drugs. Animal studies have demonstrated the potential beneficial effects of ACE inhibition at a variety of sites, including improvement of endothelial function, inhibition of platelet aggregation, prevention of atherosclerotic lesions and inhibition of myointimal proliferation, extending the concept to a more general definition of cardiovascular protection with ACE inhibitors involving both the heart and the vessels. ACE inhibitors prevent stimulation of smooth muscle cell angiotensin-II (A-II) receptors, thereby blocking both contractile and proliferative actions of A-II. In addition, ACE inhibition of kininase inhibits the breakdown of bradykinin, a direct stimulant of nitric oxide release from the intact endothelial cell. Thus, at the cellular level ACE inhibition shifts the balance of ongoing mechanisms in favour of those promoting vasodilatory, anti-aggregatory, antithrombotic and antiproliferative effects. Although these data have not all been validated in human studies, the reduction of ischemic events in studies of ACE inhibition in left ventricular dysfunction (LVD) and, more recently, also in patients without LVD, cannot be explained solely by improved hemodynamics, and it is possible that actions on the endothelium, the atherosclerotic process and platelets are at least in part responsible. So, the available data underlie the potential benefits of ACE inhibition in the field of ischemic heart disease and atherosclerosis; the results of ongoing studies in humans looking more directly at the influence of ACE inhibitors in this setting are awaited with interest.

Beta-blockade in hypertension and congestive heart failure.

Hypertension is common and increases the risk of death from coronary artery disease and cerebral vascular disease. The reason for treating hypertension is to prevent the long-term complications of this disorder. Many studies of antihypertensive therapy have produced only modest reductions in coronary events; in particular, with the use of beta-blockers. Clinical trials and meta-analyses have shown a lesser effect of these drugs on primary prevention of coronary events, cardiovascular and total mortality with respect to other antihypertensive approaches based on the use of low-dose diuretic therapy, especially in the elderly, even if the reduction of stroke and heart failure (HF) were similar. New beta-blockers with vasodilating properties due to the capacity to enhance the release of endothelial nitric oxide, then lessening a contributory mechanism to the pathogenesis of atherosclerosis as endothelial damage and dysfunction, seem to possess considerable potential in the treatment of hypertension, particularly in terms of improvement of cardiovascular outcome of patients. In HF, there is now considerable interest in the therapeutic use of beta-blockade. Some recent clinical trials have demonstrated conclusive evidence of the beneficial effects of beta-blocker therapy on survival in chronic HF. As a result of these data, beta-blocker therapy has become part of standard therapy for patients with chronic HF, in addition to angiotensin-converting enzyme-inhibitors and diuretics. The treatment is, in general, well tolerated. There are, however, some unanswered questions. One is whether some beta-blockers may be better than others. The major mortality benefit is probably a class-effect of beta1-adrenoceptor blockade, but the differences between beta-blockers might be clinically relevant. For example, it is under debate whether ancillary properties of some beta-blockers, such as the capability of exerting antioxidant effects or enhancing the nitric oxide production, may contribute to the clinical effects of these drugs. Future clinical trials will report over the next few years and help to answer the question about differences in mortality effects among types of beta-blocking agents, thus correctly defining the precise role of these drugs in the wide spectrum of cardiovascular disease.

Relationship of systemic hemodynamics, left ventricular structure and function, and plasma natriuretic peptide concentrations during pregnancy complicated by preeclampsia.

OBJECTIVE: This study was done to evaluate left ventricular structure and function among pregnant patients with preeclampsia and compare them with those of normotensive pregnant and nonpregnant subjects. It also tested the hypothesis that abnormalities in left ventricular structure and function are associated with elevated plasma levels of natriuretic peptides. STUDY DESIGN: The study compared 75 pregnant women (n = 40 with preeclampsia; n = 35 normotensive pregnant women) and 10 nonpregnant normotensive control subjects undergoing an echocardiographic and biohumoral (renin activity and aldosterone, atrial natriuretic peptide, and brain natriuretic peptide concentrations) evaluation. The statistical analysis was carried out by analysis of variance, and significance was set at P <.05. RESULTS: Comparison of pregnant patients with preeclampsia versus both normotensive pregnant women and nonpregnant women showed significant increases in left ventricular mass and left ventricular endsystolic and end-diastolic volumes and significant reductions in left ventricular ejection fraction and percentage of fractional shortening. These changes coincided with increases in plasma levels of atrial natriuretic peptide and brain natriuretic peptide that were linearly related to the left ventricular structural and functional changes observed in patients with preeclampsia. CONCLUSION: Pregnant patients with preeclampsia showed adaptation to the increase in systemic blood pressure, with significant modification of left ventricular structure and function related to the plasma levels of both atrial natriuretic peptide and brain natriuretic peptide. A simple evaluation of plasma natriuretic peptide concentrations could help to discriminate patients with preeclampsia who have a condition of mild left ventricular overload.

Effects of the administration of an angiotensin-converting enzyme inhibitor during the acute phase of myocardial infarction in patients with arterial hypertension. SMILE Study Investigators. Survival of Myocardial Infarction Long-term Evaluation.

A positive history of arterial hypertension (HBP) is present in as many as 30% of patients with acute myocardial infarction (AMI) and their clinical outcome could be greatly improved by drugs enhancing blood pressure control and preserving ventricular function. The aim of the present study was to evaluate the importance of a history of HBP on the clinical efficacy of early treatment with the angiotensin-converting enzyme (ACE) inhibitor zofenopril in patients with anterior AMI. We summarize the results of a post-hoc analysis of data from the Survival of Myocardial Infarction Long-term Evaluation (SMILE) study, which randomly evaluated the efficacy of zofenopril given within 24 h of symptom onset to patients with anterior AMI not undergoing thrombolysis. Of 1441 patients who entered the study, 565 (39.2%) had a history of HBP. The mean follow-up time was 12 months and the main outcome measures were 6-week combined occurrence of death and severe congestive heart failure (CHF) and 1-year mortality. After 6-week of treatment with zofenopril the relative risk of death or severe CHF was 0.60 (95% confidence interval [CI]: 0.45-0.81; 2P < .05) in the hypertensive group and 0.89 (0.74-1.08; 2P = .62) for normotensive patients, whereas the 1-year risk of death was 0.61 (95% CI: 0.23,0.89; 2P < .05) and 0.77 (95% CI: 0.52-1.17; 2P = .22), respectively. The 6-week prevalence of mild-to-moderate CHF was also significantly reduced by zofenopril in the hypertensive population (14.1% v 9.4%; 2P < .05). The present data suggest that treatment with zofenopril started within 24 h of the onset of anterior AMI could be highly beneficial in patients with a history of HBP.