Resuscitation of a dead cardiomyocyte

Abstract

Although cardiac resuscitation can revive the whole body, the mechanisms are unclear. To this end, we propose that reviving a dead/dysfunctional cardiomyocyte will shed light on resuscitation mechanisms and pave the way to treat cardiac myopathies. The degradation of the myocyte cytoskeleton by the proteasome system which involves calpains, ubiquitin, caspases and matrix metalloproteases is the main focus of this review. The activation of calpains beyond the calpastatin-mediated inhibition due to extensive calcium harbor can lead to titin degradation, damage to the sarcomere and contractile dysfunction. The ubiquitin proteasome system can disturb the protein homeostasis within the cell and generate a dysfunctional myocyte. The matrix metalloproteases disrupt the collagen/elastin ratio and connexins to generate arrhythmias. The concept of cardiac resuscitation stems from protecting the myocyte cytoskeleton and keeping the protein homeostasis intact through management of the degradation machinery. In this regard, proteasome inhibitors for the degradation machinery have an elegant space. Recently exosomes have been identified potentially, as carriers of microRNAs or proteins that can modify the target cells. Exosomes loaded with the inhibitor "cargo" which comprises microRNAs, siRNAs or proteins to inhibit the degradation machinery can be a method of choice for cardiac resuscitation-a process difficult to execute.

Mitochondrial Transcription Factor A's role in heart failure.

“…Alterations in cytoskeletal and contractile proteins due to calpain protease up-regulation causes the degradation of proteins such as myosin, F-actin, and titin, resulting in a disorganized sarcomere (Ellis et al 2010). The proteolytic activity of calpains leads to intracellular degradation of proteins such as Titin, an essential contractile protein of the sarcomere (Kunkel, Chaturvedi, and Tyagi 2015a).…”

“…Inhibition of the calpain protease family is an important factor mitigating molecular dysfunction within the progressively failing myocardium. Therapeutics directed towards heart failure through calpain activity/expression inhibition may elongate life of heart failure patients (Kunkel, Chaturvedi, and Tyagi 2015b).…”

“…TFAM is a promoter-specific enhancer of mtDNA, regulator of mitochondrial genes and mtDNA copy number, and a physical protector of mtDNA (Ekstrand et al 2004;Kunkel, Chaturvedi, and Tyagi 2016). TFAM packages single copies of mtDNA, creating a mitochondrial nucleoid (Kukat et al 2015;Wang et al 1999).…”

“…SERCA2a, an ATP-dependent Ca 2+ transporter, reduces free cytoplasmic Ca 2+ by storing it in the sarcoplasmic reticulum (Kunkel, Chaturvedi, and Tyagi 2015b). SERCA2a knockout models result in Heart Failure; SERCA2a activity is significant for cardiomyocyte performance and contains translational components (Heinis et al 2013;Sikkel et al 2014;Lipskaia et al 2010;Park and Oh 2013;Zsebo et al 2014).…”

“…TFAM's regulation of SERCA2a decreases cytoplasmic Ca 2+ levels, effectively decreasing protease Calpain 1 expression. Ca 2+ -driven calpain proteases are responsible for the proteolytic degradation of both contractile and cytosolic proteins (Kunkel, Chaturvedi, and Tyagi 2015a). Studies show that calpain up-regulation is a major factor in cardiomyocyte functional decline (Takahashi et al 2006).…”