Calpain is an intracellular Ca(2+)-activated protease and an important mediator of the actions of calcium Cleavage by calpain is critical in a variety of calcium-regulated cellular processes such as muscle contraction, neuronal excitability, secretion, signal transduction, cell proliferation, differentiation, cell cycle progression, and apoptosis Deregulation of calpain caused by a disruption of calcium homeostasis during cardiac pathologies such as atrial fibrillation, heart failure, hypertrophy, or ischemia reperfusion, is critically involved in the myocardial damage This review will summarize the physiologic and pathophysiologic basis of calpain Atrial fibrillation is chosen as one example to explain the specific consequences of an increased calpain activity in cardiac muscle

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1755-5922.2010.00245.x

Physiologic and Pathophysiologic Role of Calpain: Implications for the Occurrence of Atrial Fibrillation

Mitochondrial dysfunction has been reported to underline heart failure, and our earlier report suggests that mitochondrial fusion and fission contributes significantly to volume overload heart failure. Although ample studies highlight mitochondrial dysfunction to be a major cause, studies are lacking to uncover the role of mitochondrial epigenetics, i.e. epigenetic modifications of mtDNA in cardiomyocyte function. Additionally, mitochondrial proteases like calpain and Lon proteases are underexplored. Cardiomyopathies are correlated to mitochondrial damage via increased reactive oxygen species production and free calcium within cardiomyocytes. These abnormalities drive increased proteolytic activity from matrix metalloproteinases and calpains, respectively. These proteases degrade the cytoskeleton of the cardiomyocyte and lead to myocyte death. mtDNA methylation is another factor that can lead to myocyte death by silencing several genes of mitochondria or upregulating the expression of mitochondrial proteases by hypomethylation. Cardiomyocyte resuscitation can occur through mitochondrial interventions by decreasing the proteolytic activity and reverting back the epigenetic changes in the mtDNA which lead to myocyte dysfunction. Epigenetic changes in the mtDNA are triggered by environmental factors like pollution and eating habits with cigarette smoking. An analysis of mitochondrial epigenetics in cigarette-smoking mothers will reveal an underlying novel mechanism leading to mitochondrial dysfunction and eventually heart failure. This review is focused on the mitochondrial dysfunction mechanisms that can be reverted back to resuscitate cardiomyocytes.

Epigenetic revival of a dead cardiomyocyte through mitochondrial interventions.

Atrial fibrillation (AF) is associated with substantial structural changes at cell and tissue level. Cellular hypertrophy, disintegration of sarcomeres, mitochondrial swelling and apoptosis have been described as typical histo-morphologic alterations in AF. Main initiators for cellular alterations in fibrillating atrial myocytes are cytosolic calcium overload and oxidative stress. Calpains are intracellular Ca2+- activated proteases and important mediators of calcium overload. Activation of calpains and down-regulation of the calpain inhibitor, calpastatin, contribute to myocardial damage in fibrillating atria. Thus, deregulations of the expression, activity, or subcellular localization of calpain within atrial myocytes have been established as important mediators of atrial myopathy during AF.

Atrial Calpains: Mediators of Atrialmyopathies in Atrial Fibrillation.

Background Functional tricuspid regurgitation often occurs in patients with concomitant left sided, valve disease. Several types of tricuspid valve annuloplasty have been described, but there is no consensus on the management of functional tricuspid regurgitation. We report a modified annuloplasty technique and compare its efficacy with the conventional Kay technique. Methods A retrospective review was made of 60 patients who received tricuspid valve annuloplasty (group A, modified method; group B, Kay technique) and the early and midterm outcomes of modified method and Kay technique were compared. Results Three patients underwent ring annuloplasty using a semirigid Carpentier-Edwards ring due to failing suture annuloplasty. All patients were completely cured when they left the hospital. The follow-up time was (32 ± 7) months in group A and (30 ± 7) months in group B. After three years, tricuspid regurgitation decreased by more than two grades in 13 patients in group A and 11 in group B. The mean postoperative regurgitation grade in group A was lower than group B at 12, 24 and 36 months but not significantly. Three of 28 patients developed recurrent tricuspid regurgitation in group A and five of 26 patients in group B during the follow-up period (three deaths and three ring annuloplasties excluded). Freedom from recurrent tricuspid regurgitation in group A was higher than that group B at all follow-up points. Postoperative right atrium diameter, right ventricle endodiastolic dimension and tricuspid regurgitation area decreased obviously in both groups. The right ventricle endodiastolic dimension and tricuspid regurgitation area improved more significantly in group A than group B over three years of follow-up, Conclusions The modified annuloplasty technique achieved the same outcomes as the conventional Kay annuloplasty over the first three years postoperation. As this modified technique is simple and less expensive, it is another option for correction of functional tricuspid regurgitation.

A modified tricuspid valve annuloplasty technique for functional tricuspid regurgitation.

Background: Infantile spasm (IS) is a catastrophic epileptic syndrome of childhood and is usually insensitive to conventional antiepileptic drugs. Studies revealed that prenatal stress (PS) exposure and Melanocortin-2 Receptor (MC2R) may be involved in the pathogenesis of IS. However, the exact mechanism still remains unknown. Methods: In this study, PS was initially given to Wistar rats and ACTH injection was performed in offsprings. Seizure was then induced and evaluated, followed by MC2R immunohistochemistry and expression detection. Results: Significant differences in seizure number, MC2R and CRH expressions were observed among different subgroups. Conclusions: Our study suggested that PS exposure may be an important factor in the pathogenesis of IS. ACTH together with low expression of MC2R, may inhibit IS seizures.

ACTH and Low Melanocortin-2 Receptor Expression Inhibit Infantile Spasm (IS) Seizures in Prenatal Stress (PS) Exposed Rats

BACKGROUND Atrial fibrillation (AF) is accompanied by atrial structural remodeling. Calpain activity is induced during AF. To test a causal relationship between calpain activation and atrial structural changes, N-acetyl-Leu-Leu-Met (ALLM), a calpain inhibitor, was utilized in a canine AF model. METHODS Fifteen dogs were randomly divided into 3 groups: sham-operated group, control group and calpain inhibitor group; each with 5 dogs. Sustained AF was induced by rapid right atrium pacing at 600 beats per minute for 3 weeks. ALLM was administered at a dosage of 1.0 mg x kg(-1) x d(-1) in the calpain inhibitor group. Three weeks later, the proteolysis, protein expression of TnT and myosin, calpain I localization and expression and structural changes were examined in left atrial free walls, right atrial free walls and the interatrial septum respectively. Atrial size and contractile function were also measured by echocardiography. RESULTS Long-term rapid atrial pacing induced marked structural changes such as enlarged atrial volume, myolysis, degradation of TnT and myosin, accumulation of glycogen and changes in mitochondrial shape and size, which were paralleled by an increase in calpain activity. The positive correlation between calpain activity and the degree of myolysis (r(s) = 0.90 961, P < 0.0001) was demonstrated. In addition to structural abnormalities, pacing-induced atrial contractile dysfunction was observed in this study. The pacing-induced atrial structural alterations and loss of contractility were partially prevented by the calpain inhibitor ALLM. CONCLUSIONS Activation of calpain represents key features in the progression towards overt structural remodeling. Calpain inhibitor, ALLM, suppressed the increased calpain activity and reversed structural remodeling caused by sustained atrial fibrillation in the present model. Calpain inhibition may therefore provide a possibility for therapeutic intervention in AF.

Calpain I inhibition prevents atrial structural remodeling in a canine model with atrial fibrillation.

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Calpain I inhibition prevents atrial structural remodeling in a canine model with atrial fibrillation.