Translational Molecular Cardiovascular Research Program
Vision/Goals: To improve our understanding of factors that contribute to atherosclerotic plaque rupture and subsequently lead to stroke (carotid) or heart attack (coronary). To identify biomarkers predictive of plaque rupture events.
Hernan Bazan, MD FACS
Professor, Section of Vascular/Endovascular Surgery, Dept. of Surgery
Program Director, Vascular Surgery Fellowship
Ochsner Clinic, New Orleans, LA
We have a limited understanding of the mechanisms involved in atherosclerotic plaque rupture and this is a critical barrier to developing new therapies for the prevention of carotid-related stroke and myocardial infarction (MI), both of which are complications of atherosclerosis. Understanding the molecular process involved in atherosclerotic plaque rupture is important to develop possible new therapies. Furthermore, earlier detection of plaque rupture thru biomarker measurement may reduce the morbidity and mortality in these patients. However, identification of serum biomarker(s) involved during atherosclerotic plaque rupture is complicated by the lack of an adequate animal model. We have built a carotid biobank with atherosclerotic plaque and sera from patients undergoing CEAs with asymptomatic high-grade carotid disease and from patients after sustaining an acutely symptomatic ischemic event, giving us a unique view into the events occurring during plaque rupture. As of October 2015, our carotid biobank has over 220 unique patient samples.
Atherosclerotic carotid plaque rupture is preceded by thinning of the fibrous plaque and thought to be due to loss of vascular smooth muscle cell volume. MicroRNAs (miRNAs) can regulate gene expression and protein translation, providing new venues for therapeutic targets. Two microRNAs (miRs), miR-221 and miR-222, target the cyclin-dependent kinase inhibitor, p27Kip1, which promotes intimal thickening in atherosclerotic plaques. miRs are non-coding RNAs (ncRNAs), a novel class of endogenous, small RNAs that negatively regulate gene expression via degradation or translational inhibition of their target transcripts (mRNAs). Furthermore, circular RNAs (circRs) have recently been discovered to regulate miRNAs by acting as ‘sponges’ or decoys, further regulating gene expression. circR-16 is a putative inhibitor of miR-221/222 activity.
Our preliminary data suggests a role for circRNA in the regulation of miRNA in plaque development. Our own data suggest that expression of two microRNAs (miR-221/222) is diminished and circRNA-16, an inhibitor of miR-221/222, is increased in atherosclerotic plaque rupture. This points toward down-regulation of miR-221/222 activity playing an important role in the macrophage response to plaque rupture. Our ongoing research will identify the mechanisms by which loss of miR-221/222 and increased circRNA-16 lead to plaque destabilization. The serum changes may offer novel venues for serum detection of atherosclerotic plaque rupture. As it is likely that other ncRNAs (i.e. microRNAs, circRNAs) are uniquely involved in both asymptomatic carotid disease and during carotid plaque rupture. Ongoing array-based transcriptome studies aim to address these other novel ncRNAs, whose expression is altered following atherosclerotic plaque rupture.
Ongoing Projects (Active Grant Support)
1) ‘Biomarkers during carotid plaque rupture: Transcriptomic and lipidomic approaches for their discovery’
Identification of novel non-coding RNAs and pro-inflammatory lipid mediators in sera of patients that present with acute carotid plaque rupture
2) ‘Alteration of the transcriptome during acute atherosclerotic plaque rupture’
Roles of new non-coding RNAs (microRNAs and their inhibitory circularRNAs) in carotid plaque rupture
3) ‘‘Plaque destabilization through shear stress mediated changes in non-coding RNA’
Elucidation of the roles of novel non-coding RNAs (microRNAs and their inhibitory circularRNAs) in acutely symptomatic carotid plaques
Support the Research Work
A gift to the Bazan lab helps support research to treat complications of atherosclerosis, such as strokes and peripheral arterial disease.