Apoptosis, Necrosis, and Necroptosis – Are They Important in Vascular Injury?

Have you ever wondered the difference between necrosis and apoptosis and how that relationship relates to vascular injury? What about whether they can be one and the same at any point in the cell death process?

Cellular death can be either natural or trauma induced.  The primary difference between the two is that the necrotic pathway consist of the premature death of cells and tissue from a cause of factors, such as infection, toxins, or trauma. Necrosis can often time lead to the detriment of the organ system and/or organism.  Whereas, apoptosis provides beneficial effects to the organism –  a process of programmed cell death that is a result of housekeeping pathways.  It produces cell fragments called apoptotic bodies that engulf and remove contents of a damaged cell before it can become toxic to an organism.  For example, in the vessels, macrophages engulf oxidized low density lipoproteins (oxLDLs) resulting in foam cells. These oxLDL are not metabolized properly causing the cell to undergo apoptosis. The result is chronic inflammation.

With that being said, the apoptotic pathway acts in the Fas receptor (Apo-1 or CD95) in the binding site of the transmembrane protein part of the fas ligand (FasL).  Interaction between Fas and FasL results in the formation of a death-induced signaling complex.  A primary mechanistic cause of cell death is the proteolytic caspases; enzymes that initiating the degradation of the cellular organelles leading to cell shrinkage and rounding due to the proteinaceous cytoskeleton by caspases.  The caspases that are suggested to initiate this programing are FADD, caspase-8 and caspase-10. However, there are other pathways that can induce apoptosis, which are not lucid.  Since FasL plays an important role in the immune system and the progression of cardiovascular disease and cancer, it will bind to TNF to induce apoptosis of the immune cells in attempt to increase the number of healthy cells and, in the case of atherosclerosis, eliminate the lipid laden cells in the vessel wall.

Necroptosis is a relatively novel form of necrosis. This pathway suggests necrosis can be programmed, favoring the immunogenic nature of defense against a pathogen by the immune system. Being a caspase independent pathway, necroptosis allows cells to undergo the suicide process in the presence of viral caspase inhibitors to contain the virus to a specific region. Necroptosis has been shown to play a role in disease processes such as autoimmune diseases, pancreatitis, and myocardial infarction using TNFα and its receptor TNFR1 that is associated with TRAF2 signaling. Phosphorylation of MLKL allows for the insertion of permeabilized plasma membranes leading the release of damage-associated molecular patterns initiating the inflammatory response. The growing relevance of necroptosis is the pathophysiology can lead to the understanding of many pathologies such as acute tissue damage including hypertension, myocardial infarction, stroke, ischemia-reperfusion injury, and atherosclerosis as well as some cancers. Ischemia-reperfusion injury is a major burden of organ transplants, thus contributing to tissue damage resulting from activation of the necroptosis pathway. Understanding this pathway, could be a seductive means of controlling vascular injury.

What are your thoughts on this topic? I am interested in learning more about this as a viable research focus for the cardiovascular therapeutic area.



Vascular Calcification… It’s Complicated

The Vascular Discovery meeting in San Francisco last week was whirlwind of learning and networking. My favorite moment was at the Friday 7 am Early Career Training session where, by coincidence, I ended up at the same table with @Ritu_Ganguly1, @MoradiShayan and @JeffHsuMD. We had all signed up to provide social media coverage of the conference via the Twitter account of the Journal of the American Heart Association (JAHA), so it was great to meet them in person. Later in the day, Ritu and I worked (read: laughed and cried) through the Genome Editing Bootcamp together, a challenging case-based workshop led by the excellent Dr. Kiran Musunuru.

As discussed in my pre-conference blog, vascular research is extremely pertinent to chronic kidney disease. Children on dialysis can manifest the same arterial calcification as a 70 year old. An established mechanism in vascular calcification is the phenotype switch where vascular smooth muscle cells start behaving like bone cells, secreting matrix vesicles filled with calcium-phosphate mineral into the extracellular matrix. At the Vascular Discovery meeting Dr. Elena Aikawa discussed advances made in the understanding of matrix vesicles, which are critical precursors of microcalcifications. In a JCI paper, her group reported co-localization of the protein sortilin with caveolin-1 and tissue nonspecific alkaline phosphatase, and defined sortilin’s role in loading mineral into vesicles. Dr. Aikawa raised a follow up question: Would future therapies that block activation of sortilin prevent microcalcifications, and thus prevent vascular calcification?

Dr. Catherine Shanahan, who described the role of programmed cell death or apoptosis in dialysis-associated vascular calcification, discussed the interaction of aging and vascular cell phenotype change at her Vascular Discovery talk. Her lab has been examining the nuclear lamina, or network of filament proteins which are a part of the cell nucleus. It turns out that the aging vascular smooth muscle cell accumulates prelamin A (see Circulation Research paper), which leads to DNA damage and triggers the osteogenic phenotype switch. This raises the intriguing question: Can we reverse cell aging to block vascular calcification?

The nature of scientific research is that more questions are raised as progress is made. Scientific meetings such as Vascular Discovery have an important role in updating investigators and clinicians, fostering new collaborations and training early career professionals.

Wei Ling Lau Headshot

Wei Ling Lau, MD is Assistant Professor in Nephrology at University of California-Irvine. She is currently funded by an AHA Innovative Research Grant, and has been a speaker for CardioRenal University and the American Society of Nephrology. Follow her on Twitter @Kidneys1st