Granzymes in cardiovascular injury and disease

Chronic inflammation and impaired wound healing play important roles in the pathophysiology of cardiovascular diseases. Moreover, the aberrant secretion of proteases plays a critical role in pathological tissue remodeling in chronic inflammatory conditions. Human Granzymes (Granule secreted enzymes - Gzms) comprise a family of five (GzmA, B, H, K, M) cell-secreted serine proteases. Although each unique in function and substrate specificities, Gzms were originally thought to share redundant, intracellular roles in cytotoxic lymphocyte-induced cell death. However, an abundance of evidence has challenged this dogma. It is now recognized, that individual Gzms exhibit unique substrate repertoires and functions both intracellularly and extracellularly. In the extracellular milieu, Gzms contribute to inflammation, vascular dysfunction and permeability, reduced cell adhesion, release of matrix-sequestered growth factors, receptor activation, and extracellular matrix cleavage. Despite these recent findings, the non-cytotoxic functions of Gzms in the context of cardiovascular disease pathogenesis remain poorly understood. Minimally detected in tissues and bodily fluids of normal individuals, GzmB is elevated in patients with acute coronary syndromes, coronary artery disease, and myocardial infarction. Pre-clinical animal models have exemplified the importance of GzmB in atherosclerosis, aortic aneurysm, and cardiac fibrosis as animals deficient in GzmB exhibit reduced tissue remodeling, improved disease phenotypes and increased survival. Although a role for GzmB in cardiovascular disease is described, further work to elucidate the mechanisms that underpin the remaining human Gzms activity in cardiovascular disease is necessary. The present review provides a summary of the pre-clinical and clinical evidence, as well as emerging areas of research pertaining to Gzms in tissue remodeling and cardiovascular disease.