Apoptosis and efferocytosis as mechanisms of impaired fibrotic tissue repair in diabetes associated vascular complications

Background

Type 2 diabetes (T2D) patients have a 2-4-fold higher risk to die due to an aggravated atherosclerotic disease. Yet, which biological factors that drive the formation of high risk plaques in T2D remain unknown.

We provided evidence for an impaired fibrous tissue repair as a cause of high-risk plaque formation in T2D. This has been supported by imaging studies showing thin fibrous caps and large cores of dead cells in T2D plaques, suggesting a link between cell death and impaired tissue repair. Apoptosis and the removal of apoptotic cells (efferocytosis) are crucial for tissue repair and we recently showed that these processes are key factors in plaque progression and ruptures.

Here I aim to identify biological changes underlying the impaired tissue repair in T2D, focusing on apoptosis and efferocytosis. I aim to explore -If plaque apoptosis predicts cardiovascular events and if circulating apoptosis markers predict T2D plaque progression

-Key apoptosis/efferocytosis pathways affected by T2D and if these pathways can be targeted therapeutically to stimulate tissue repair -T2D induced transcriptional and functional differences in key cell populations affecting efferocytosis

-Arterial tissue repair, focusing on protein composition, growth factors and how key apoptosis/efferocytosis pathways affect T2D tissue repair Workplan

Carotid plaques, blood and follow up is available in the CPIP biobank (n>1300). Carotid imaging, follow-up and blood is available in the MDC-CC (n>6000) and SUMMIT (n>1500) cohorts. Apoptosis/efferocytosis in situ will be assessed by ELISA/confocal imaging.

Key apoptosis/efferocytosis/repair pathways will be identified by human plaque bulk- and single cell sequencing (RNAseq) and located with spatial RNAseq.

Functional roles of key genes/pathways and if they can be targeted therapeutically will be studied using plaque cells, cell lines and mouse models.

Apoptosis/efferocytosis markers and growth factors will be assessed by proximity extension assays and plaque progression by carotid ultrasounds. Key efferocytosis plaque cell populations will be assessed by CyTOF and single cell RNAseq. Mass spectrometry will assess matrix composition and repair. Significance

The identification of biological differences underlying atherosclerotic complications in T2D is crucial. By understanding how apoptosis and efferocytosis affect T2D tissue repair we aim to identify new therapeutic targets and biomarkers to prevent complications.