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Novel mechanisms of atherosclerotic plaque (in)stability governed by smooth muscle cells

Project leader

Forskarassistent

Ljubica Matic

Enhet: Kärlkirurgi
E-post: ljubica.matic@ki.se

PhD Students

Doktorand

Urszula Rykaczewska

Enhet: Kärlkirurgi
E-post: urszula.rykaczewska@ki.se

FOU-praktikant

Till Seime

Enhet: Kärlkirurgi
E-post: till.seime@ki.se

Doktorand

Eva Karlöf

Enhet: Kärlkirurgi
E-post: Eva.Karlof@ki.se

Doktorand

Bianca Suur

Enhet: Kärlkirurgi
E-post: bianca.suur@ki.se

Unstable atherosclerotic plaques in the carotid bifurcation cause cerebrovascular embolism and stroke. During atherogenesis, contractile smooth muscle cells (SMCs) in the normal media respond to accumulation of lipids and inflammation and become activated into a secretory/replicating phenotype engaging in intimal remodeling and plaque fibrous cap formation. Quiescent SMCs express a unique repertoire of markers, including smooth muscle actin, mostly associated with the acto-myosin cytoskeleton. These markers are downregulated in activated SMCs and permanently suppressed in the fibrous cap, while they reappear in vascular repair processes (intimal hyperplasia). Distinct features of SMCs in the plaque environment are determined by the surrounding inflammatory and lipid mediators as well as calcium deposits, and may ultimately induce their transdifferentiation into other cell types and restrict their capacity to maintain fibrous cap stability. Currently, there are no sensitive markers to demarcate the early changes in SMC phenotype, a problem that has been addressed by both us and others. Based on this, our research aims are to:

  1. Unravel novel information on molecules and pathways regulating SMC function in atherosclerosis, using human biobank resources
  2. Investigate these molecules with an integrative approach using animal and cell culture models
  3. Translate some candidates into targets for development of plaque stabilizing therapies, diagnostic protocols or imaging modalities aimed at early detection of vulnerable plaques and patients.

To achieve this we have organized an integrative workflow based on 1) discovery by correlating clinical parameters to deep large-scale molecular profilings of plaque tissue and plasma from a biobank of patients undergoing surgery for carotid atherosclerosis (BiKE), combined with 2) functional and mechanistic studies in murine/zebrafish models of vascular injury and cell culture, followed by 3) replication in independent cardiovascular cohorts and public resources. The unique feature of this project lies in entry from human data by unbiased mining for molecular predictors of unstable atheroma. This project will enable us to understand how SMC activation is affected by, and in turn modulates the local environment leading to plaque rupture, which will open possibilities for improved therapy or diagnostic imaging to prevent complications of end-stage atherosclerosis.