The Pathogenesis of Myocardial Cell Death via Autophagy, Necrosis and Apoptosis
Cardiovascular disease and its accompanying disorders, myocardial infarction, and heart failure are leading causes of mortality worldwide. Cell death is a hallmark for cardiovascular disease as its progressive or acute pathogenesis leads to ventricular dysfunction, heart failure, and myocardial infarction. Conditions such as hypertension, coronary artery disease, diabetes, obesity, genetic mutations of cellular architecture, and infections can cause oxygen deprivation, myocardial infarction, and heart failure with subsequent loss of myocytes. Cardiac myocytes undergo cell death and removal by mechanisms called autophagy, apoptosis, and necrosis. In this essay, the pathogenesis of myocardial cell death via autophagy and necrosis will be discussed with an examination of apoptosis.
Autophagy is the catabolic process and regulation of dysfunctional cells via the formation of autophagosomes to lysosomes for degradation. Injuries such as myocardial infarction interrupt blood flow and oxygenation causing myocyte death. The mechanism of autophagy activates as a protective measure and reuptakes broken down components like proteins and lipids to provide energy to remaining cells during starvation and stressful periods.
Necrosis ensues when an external factor like infection/trauma causes a traumatic cellular response with unregulated cell death. Myocyte cell necrosis occurs due to sustained calcium stress and chronic activation of adrenergic receptors which triggers necrotic cell death. When necrosis occurs, cells undergo mitochondrial changes with loss of plasma membrane integrity, cellular and organellar swelling, inflammation, and a decrease in ATP levels. The disruption of the cellular membrane and loss of its integrity releases cellular content triggering a secondary inflammatory response. Apoptosis is a programmed cellular process that causes cell death; the cells shrink, fragment into apoptotic bodies, and are engulfed via phagocytosis by macrophages and/or neighboring cells. The process of apoptosis is refined as cells can delete themselves within its tissue, maintain adequate ATP levels, and bypass the inflammatory process. Though apoptosis is an essential regulatory process for proliferating cells, cardiac apoptosis can become dysregulated and potentiate damage. Cardiomyocytes cannot proliferate once fully developed, but sustained cardiac stressors can induce protein synthesis and activate the tumor necrosis factor (TNR) causing myocyte loss, myocyte hypertrophy, and acceleration of apoptosis.
Cell death involves an extrinsic pathway by surface death cell receptors (DR) or an intrinsic pathway via the breakdown of cellular mitochondrial. In the extrinsic pathway, the binding of death ligands FAS and TNR to DR mediate induction of apoptosis or necrosis depending on the complex formed: the death-inducing signaling complex (DISC) and complex I. The DISC triggers extrinsic pathway apoptosis. Complex I can trigger intrinsic pathway apoptosis or necrosis. The DISC complex formation promoting apoptosis provokes a cascade of reactions such as the activation of specific proteases called caspases to generate specific cellular reactions. These caspases cleave and cut multiple cellular proteins leading to DNA degradation and apoptotic death via phagocytosis by macrophages. In the setting of Complex I formation, cell death can undergo apoptosis or necrosis when complex I transcribe to complex II. Complex II triggers apoptosis by protease activation of procaspase-8 leading to cellular protein cleavage and proteolysis. Complex II can elicit necrosis by binding to Receptor Interacting Protein 1 and 3 causing mitochondrial permeability and damage.
In the intrinsic mitochondrial pathway of apoptosis, the outer mitochondrial membrane is permeable from the release of mitochondrial apoptogens to the cytoplasm. In the intrinsic mitochondrial pathway of necrosis, stressful stimuli such as Ca2+ influx due to reactive oxygen species and alkalosis open the mitochondrial permeability transition pore in the inner membrane. This disintegrates the electrical gradient within the membrane causing loss of ATP and fluid influx causing mitochondrial swelling.
