Identification of microRNAs 758 and 33b as potential modulators of ABCA1 expression in human atherosclerotic plaques.

BACKGROUND AND AIM: Adenosine triphosphate (ATP)-binding cassette (ABC) transporters A1 and G1 are the main transporters involved in macrophage cholesterol efflux. The understanding of the molecular mechanism(s) of their regulation in atherosclerosis is crucial for potential therapeutic approaches. Preclinical studies support a role for microRNAs in the posttranscriptional regulation of these transporters; however, no evidence is still available on human atherosclerosis. Thus, the aim of this study was to investigate the modulation of the ABCA1 and ABCG1 pathway in human atherosclerotic plaques and microRNA involvement in its modulation. METHODS AND RESULTS: Thirty-one human atherosclerotic plaques were obtained from patients undergoing carotid endarterectomy for high-grade (>70%) vessel stenosis, and divided into normocholesterolemic (n = 15) and hypercholesterolemic groups (n = 16) according to the presence/absence of hypercholesterolemia. Both ABCA1 and ABCG1 messenger RNAs (mRNAs) were significantly upregulated in carotid plaques from hypercholesterolemic patients as assessed by real-time polymerase chain reaction (RT-PCR). Despite this result, no difference was found at the protein levels analyzed by Western blot, thus suggesting a strong posttranscriptional modulation. MicroRNA microarray and subsequent validation by RT-PCR showed a significant upregulation of ABCA1-linked miR-758 and miR-33b in plaques from hypercholesterolemic patients. CONCLUSION: We provide evidence of a strong posttranscriptional regulation of ABCA1 and ABCG1 expression in human atherosclerotic plaques from hypercholesterolemic patients. This effect is potentially due to the concomitant increase of miR-33b and miR-758, two well-established regulators of ABCA1 and ABCG1 expression. The identification of miR-33b and miR-758 as putative key regulators of ABCA1 protein expression within human atherosclerotic plaques provides further data for the realization of new anti-atherosclerotic drugs with specific targets based on anti-miRNA technologies.

New aldosteron receptor inhibitors in heart failure.

This report summarizes the new therapeutic approaches in post-ischaemic heart failure given the important sanitary and socioeconomic impact resulting from the clinical management of this syndrome. Ventricular remodeling, causing changes to left ventricular anatomy and function, is the major cause of heart dysfunction. The physio-pathological role of the renin-angiotensin-aldosterone system has emerged from experimental studies and has been confirmed by the efficacy of ACE-inhibition. Although treatment with spironolactone (a non selective aldosterone antagonist) significantly reduces both the hospitalization and the mortality of NYHA III patients, this compound has important side effects. In this review we examine the efficacy of eplerenone, a new aldosterone receptor antagonist, with a more selective activity with respect to spironolactone. Several studies versus placebo have demonstrated that this molecule, alone or in combination with anti-hypertensive drugs, is very effective in left ventricular hypertrophy and in post-ischaemic heart failure treatment. In particular, we will consider the EPHESUS as the most important study both for the size of patient group and for the experimental plan. Finally, as regards the culture and experience of single physicians, a simple flow chart of the therapy of post-ischaemic heart failure is proposed.

Severity of human hypertension in relation to the age in which high blood pressure makes its presumptive appearance.

PURPOSE: The present study investigates the properties of blood pressure (BP) circadian rhythm (CR) in newly-diagnosed hypertensives (NDH) as a function of the chronological age in which hypertension became manifest. MATERIALS AND METHODS: The study was performed on 141 NDH (71 males and 70 females, ranging in age from 24 year to 79 years), who were monitored in their 24-h BP via a non-invasive, ambulatory, automated recorder. The relation between the properties of BP CR and the age of the development of hypertension was investigated via the Clinospectror method, a trend analysis (periodic-linear regression method) for rhythmic biophenomena. RESULTS: A trend was detected for each one of the three properties of BP CR in relation with the age in which high BP made its appearance. As a matter of fact, the daily mean level (mesor) of BP CR was seen to be progressively less pronounced. The amplitude was found to show a progressive increment of its extent. The acrophase was seen to show a progressive antemeridian rotation of its timing. CONCLUSIONS: These trends suggest that hypertension tends to be less severe when its development occurs in subjects older in age. Such a less pronounced severity is, however, accompanied by a more pronounced oscillation of BP values during the 24-h of the day. Such a higher circadian variability, in turn, tends to show its highest expression during the morning hours of the day.

Prevalence of human herpesvirus (HHV)-8 infection among carriers of cardiovascular disease.

Infectious agents, such as herpesviruses, have been hypothesized to be involved in development of atheromatous plaque. The study aim was to evaluate the possibility that HHV-8 infection could be an additional risk factor for the establishment of cardiovascular disease. HHV-8 seroprevalence was determined by immunofluorescence in a population of cardiovascular disease patients (n=50) as compared to an age- and sex-matched group of control subjects (n=47); HHV-8 genome was detected in DNA extracted from circulating PBMC and from atheromatous lesions by PCR with primers specific for the minor virus capsid gene (ORF 26). The seroprevalence of HHV-8 was significantly increased in the patients as compared to the control population, while the presence of HHV-8 genome was observed in PBMC from 2 patients and 1 control. Virus-specific DNA was found in 2 out of 4 atheromatous plaques. The higher seroprevalence in patients suffering from vascular diseases as compared to age-and sex-matched controls suggests that HHV-8 infection could be an additional risk factor for the establishment of cardiovascular disease, although the data on the persistence of viral DNA in PBMC or in the arterial lesions are too exiguous to definitively support this hypothesis. More extensive studies are needed to define the exact role of HHV-8 infection in the establishment and progression of atheromatous lesions.

Further evidence against the implication of active cytomegalovirus infection in vascular atherosclerotic diseases.

The possible contribution of cytomegalovirus (CMV) to pathogenetic events associated with atherosclerotic lesion establishment and progression is still controversial. We evaluated the possibility that active ongoing CMV infection could be correlated to evolution of unstable atheromatous lesion, by analyzing patients suffering from unstable angina (n=61), acute myocardial infarction (n=43), stable angina (n=26) and peripheral arteriopathy (n=22) as compared to healthy subjects (n=30). Particularly, we assessed: past exposure to CMV by evaluating anti-CMV IgG antibodies; ongoing CMV infection by evaluating anti-CMV IgM antibodies and circulating interleukin (IL)-8 in serum; and CMV DNAemia in peripheral blood mononuclear cells (PBMC). Mean IgG values were significantly increased in patients from all groups, as compared to healthy subjects. CMV-specific IgM, as well as CMV DNAemia, were undetectable in both controls and patients. Circulating IL-8, significantly elevated in a group of individuals experiencing active CMV infection, was not significantly higher in cardiovascular disease patients, as compared to control subjects. These findings confirm previous evidence from the increased exposure to CMV infection in patients with atheromatous lesions. However, they provide further evidence against a direct implication of active systemic CMV infection in the pathogenesis of cardiovascular diseases, particularly those involving plaque instability.