Resuscitation of a dead cardiomyocyte
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Published on: March 30, 2022
George H Kunkel1, Pankaj Chaturvedi2, Suresh C Tyagi1
1Department of Physiology and Biophysics, Health Sciences Centre, A-1216, School of Medicine, University of Louisville, 500, South Preston Street, Louisville, KY, 40202, USA.
Insights
Reviving cardiomyocytes by protecting their cytoskeleton and protein balance is key to cardiac resuscitation. Managing cellular degradation machinery, potentially with proteasome inhibitors or exosome delivery, offers new therapeutic avenues for heart conditions.
Area of Science:
- Cardiovascular Biology
- Cellular Mechanisms
- Proteostasis
Background:
- Cardiac resuscitation mechanisms remain poorly understood.
- Myocyte cytoskeleton degradation contributes to cardiac dysfunction.
- Understanding cardiomyocyte revival is crucial for treating cardiac myopathies.
Purpose of the Study:
- To review the mechanisms of cardiomyocyte degradation.
- To explore strategies for protecting the myocyte cytoskeleton and protein homeostasis.
- To propose novel approaches for cardiac resuscitation.
Main Methods:
- Review of literature on proteasome system, calpains, ubiquitin, caspases, and matrix metalloproteases in myocytes.
- Analysis of calcium-induced calpain activation and its effects on sarcomeric proteins.
- Examination of the role of ubiquitin proteasome system in protein homeostasis.
- Investigation of matrix metalloproteases in collagen, elastin, and connexin disruption.
Main Results:
- Calpain activation leads to titin degradation, sarcomere damage, and contractile dysfunction.
- Ubiquitin proteasome system dysregulates protein homeostasis, causing myocyte dysfunction.
- Matrix metalloproteases disrupt extracellular matrix and cell-cell communication, inducing arrhythmias.
- Protecting myocyte cytoskeleton and protein homeostasis is central to cardiac resuscitation.
Conclusions:
- Management of degradation machinery, including proteasome inhibitors, is a promising strategy.
- Exosomes loaded with inhibitors offer a potential method for targeted cardiac resuscitation.
- Further research into exosome-based therapies could revolutionize cardiac resuscitation and myopathy treatment.
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.
