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Townsend: Cancer to cardioprotection – hearts and flowers, death and STATs

Chronic diseases such as cardiovascular disease, cancer and even ‘inflammation’ are major causes of death worldwide and the significance of our lifestyle and diet in curbing these diseases is becoming clear. Moreover, we have learned incredible amounts of information from researching cancer and then applying it to fields that are not as well investigated, such as the underlying molecular biology of cardiac disease. This presentation will explain the role of genetically induced cell death and cell death caused by blunt trauma in a variety of biomedical contexts, with a focus on cancer and cardiovascular disease.

There are three basic morphologically distinct forms of cell death that occur in tissue: necrosis, apoptosis and autophagy.

Necrosis is uncontrolled cell death that occurs when cells are exposed to extreme physiological conditions, such as respiratory poisoning or hypoxia, resulting in damage to the plasma membrane. There is a rapid loss of cellular homeostasis leading to accumulation of water and electrolytes, causing rapid swelling and cell membrane rupture. This leads to an outflow of cellular material and extensive damage to surrounding cells, inducing an inflammatory response. For example, in the heart, prolonged loss of oxygen (ischaemia) has been associated with an increase in the level of necrotic cardiomyocytes, the ‘pumping’ cells of the heart. Extensive ischaemia alone can kill myocytes by necrosis but is it debatable whether the reperfusion process can activate this cell death pathway.

Autophagy occurs at low levels under normal conditions and is important for maintaining tissue homeostasis. The process is an important survival mechanism that is rapidly activated in response to starvation, when fatty acids and amino acids from long-lived proteins, organelles and lipids that are necessary for survival are recycled. Autophagy involves the sequestration of large double-membrane vesicles called autophagosomes, which fuse with a lysosome, thus combining their internal vesicle networks. Subsequently, the contents of the autophagosome are then degraded by hydrolases and reused. For example, the response of autophagy in the heart during myocardial infarction (heart attack) is quite complex. Enhanced levels of autophagy have been observed in cardiomyocytes after ischaemia/reperfusion injury in both a pro-survival and a pro-death manner. It promotes survival under mild stress conditions with low levels of oxidative stress by removing and recycling damaged organelles in order to maintain energy levels and protein synthesis. In contrast, under severe ischaemia and reperfusion conditions there is a prolonged up-regulation of autophagy leading to excessive self-digestion of essential organelles and proteins, further enhancing cell death.

Apoptosis is a highly regulated, programmed form of cell death that requires energy to remove damaged cells without an inflammatory response. This process of cell death is also a biologically important activity, involved in cell proliferation and differentiation for the control of tissue and organ homeostasis during development, and thus is a critical component of cancer. Apoptosis is characterized by condensation of the nucleus, cell shrinkage resulting from reduction of the cytoplasm and membrane blebbing. Extensions assemble around the membrane, eventually forming membrane-enclosed vesicles termed apoptotic bodies; these contain processed organelles and nuclear fragments. This process ensures that the cell destroys itself from within and avoids leakage of contents into the extracellular space. These vesicles are rapidly recognized and phagocytized by adjacent cells or macrophages.

Apoptosis is activated by multiple stressors found in health and disease such as cytokine production, increased oxidative stress and DNA damage. Apoptosis represents a potentially preventable form of cell death, owing to its active nature, and, as such, has important therapeutic implications for new biomedical treatments.

This presentation will show some insights into these processes and how we are trying to tackle these devastating diseases using Mother Nature as our guide.





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