activation of the ERK, JNK, and p38 kinase pathways also contributes to angiogenesis. Additionally, PPIA induces cell migration and proliferation in smooth muscle. In the case of T cells, PPIA regulates the T-cell-specific tyrosine kinase ITK upon T-cell receptor stimulation. Clinical significance The PPIA protein is an important apoptotic constituent. During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response. It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells. As a proinflammatory cytokine, PPIA is highly involved in acute and chronic inflammatory diseases, including sepsis, atherosclerosis, and rheumatoid arthritis. Thus, therapeutic targeting of PPIA with selective inhibitors may prove effective in combatting such inflammatory diseases and symptoms. Correlation between plasma PPIA levels and hyperglycemia symptoms also promotes utilization of PPIA as a biomarker for diabetes and vascular disease. Furthermore, PPIA is involved in cerebral hypoxia-ischemia by contributing to the nuclear transport of AIF, a proapoptotic factor, in neurons. To maintain the integrity of the blood brain barrier and mitigate brain injury, PPIA helps to recruit circulating monocytes and stimulates survival and growth pathways. In cardiac myogenic cells, cyclophilins have been observed to be activated by heat shock and hypoxia-reoxygenation as well as complex with heat shock proteins. Thus, cyclophilins may function in cardioprotection during ischemia-reperfusion injury. Currently, PPIA expression is highly correlated with cancer pathogenesis, but the specific mechanisms remain to be elucidated. PPIA overexpression has been associated with hepatocellular