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

Xue, Hong-Jie; Liu, Weimin; Li, Yue; Gong, Yanling; Yang, Baofeng; Jin, Chengluo; Sheng, Li; Chu, Shan; Zhang, Li; Shan, Hongbo; Liu, Jie

doi:10.1097/00029330-200801010-00007

Cited by 5 publications

(5 citation statements)

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“…Though the focus of their study was not mitochondrial dynamics, it is stated that the cardiomyocyte mitochondria were misshaped and differentially sized (60). We assume that this change in shape may lead to mitochondrial impairment.…”

Section: Mitophagy and Heart Failurementioning

confidence: 99%

Epigenetic revival of a dead cardiomyocyte through mitochondrial interventions

Kunkel¹,

Chaturvedi²,

Tyagi³

2015

Biomolecular Concepts

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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.

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Section: Mitophagy and Heart Failurementioning

confidence: 99%

Epigenetic revival of a dead cardiomyocyte through mitochondrial interventions

Kunkel¹,

Chaturvedi²,

Tyagi³

2015

Biomolecular Concepts

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“…AFib results in cytosolic calcium overload resulting in increased calpain activity (45)(46)(47)(48). Calpain activity in AFib has been correlated with both increased apoptosis and myofilament destruction (46,48,49). Calpain inhibition corrects the increase in apoptosis of the atrial myocytes in AFib (46).…”

Section: Calpain Activation and Upregulation Has Been Implicated In S...mentioning

confidence: 99%

Proteolytic degradation of atrial sarcomere proteins underlies contractile defects in atrial fibrillation

Cizauskas,

Burnham,

Panni

et al. 2023

Preprint

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(ii) ABSTRACTAimsAtrial fibrillation (AFib) is the most common cardiac rhythm disturbance. Treatment of AFib involves restoration of the atrial electrical rhythm. Following rhythm restoration, a period of depressed mechanical function known as atrial stunning occurs that involves decreased blood flow velocity and reduced atrial contractility. This suggests that defects in contractility occur in AFib and are revealed upon restoration of rhythm. The aim of this project is to define the contractile remodeling that occurs in AFibMethods and ResultsTo assess contractile function, we used a canine atrial tachypacing model of induced AFib. Mass spectrometry analysis showed dysregulation of contractile proteins in samples from AFib compared to sinus rhythm atria. Atrial cardiomyocytes showed reduced force of contraction in skinned single cardiomyocyte calcium-force studies. There were no significant differences in myosin heavy chain isoform expression. Resting tension is decreased in the AFib samples correlating with reduced full-length titin in the sarcomere. We measured degradation of other myofilament proteins including cMyBP-C, actinin, and cTnI, showing significant degradation in the AFib samples compared to sinus rhythm atria. Many of the protein degradation products appeared as discrete cleavage products that are generated by calpain proteolysis. We assessed calpain activity and found it to be significantly increased. Skinned cardiomyocytes from AFib atria showed decreased troponin I phosphorylation, consistent with the increased calcium sensitivity that was found within these cardiomyocytes.ConclusionsWith these results it can be concluded that AFib causes alterations in contraction that can be explained by both molecular changes occurring in myofilament proteins and overall myofilament protein degradation. These results provide an understanding of the contractile remodeling that occurs in AFib and provides insight into the molecular explanation for atrial stunning and the increased risk of atrial thrombus and stroke in AFib.

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“…Based on in vitro studies, a number of cellular proteins have been identified as potential calpain substrates (Table 3). These include a large number of cytoskeletal and myofibrillar proteins (spektrin, troponin) [40,45,[61][62][63], membrane-associated proteins (receptors, ion channels) [64][65][66][67][68][69][70][71][72][73][74], metabolic enzymes [75,76], signaling modulated kinases and phosphatases (PKC, calcineurin) [77][78][79][80][81][82], some transcription factors [83,84], and proteins involved in apoptotic signaling [23,[85][86][87][88][89][90][91][92]. Hence, calpain can play an important regulatory role in processes including remodeling of cytoskeletal proteins, signal transduction pathways, degradation of enzymes controlling progression through the cell cycle, regulation of gene expression, and apoptotic pathways.…”

Section: Physiological and Pathophysiological Functionmentioning

confidence: 99%

“…However, calpain inhibitor I shows stronger inhibitory effects toward m‐calpain, whereas calpain inhibitor II is more potent toward μ‐calpain. Both compounds are reversible and competitive inhibitors [40,41] (Table 2). To increase specificity, new inhibitors have been designed.…”

Section: Activation Mechanism Of Calpainmentioning

confidence: 99%

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

Bukowska

Lendeckel

Bode‐Böger

et al. 2010

Cardiovascular Therapeutics

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SUMMARYCalpain 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.Calpain is an intracellular Ca 2+ -activated protease and an important mediator of the actions of calcium. This protease is regarded as a modulator protease and hydrolyzes substrates in a limited manner, modulates thereby their activities, specificities, structures, intracellular localizations, and half-life. This regulated 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 [1][2][3][4][5]. Deregulation of calpain caused by a disruption of calcium homeostasis during cardiac pathologies such as atrial fibrillation (AF), heart failure, hypertrophy, or ischemia reperfusion, is critically involved in the myocardial damage. General Properties of the Calpain FamilyFor several years, calpain has been described under different names: Ca 2+ -dependent neutral protease [6], kinase-activating factor (KAF) [7], calcium-activated sarcoplasmic factor hydrolyzing Z-lines (CaSF) [8], protein kinase C-activating factor [9], or calcium-activated neutral protease (CANP) [10]. Finally, Suzuki unified the different designations as calpain (calcium iondependent papain-like cysteine protease) in 1991 [11].The classical calpains are heterodimers composed of a large 80 kDa catalytic subunit (80K encoded by CAPN1 (EC3.4.22.52) and CAPN2 (EC3.4.22.53) for μ-and m-calpains, respectively) and a common 30 kDa regulatory subunit (30K encoded by CAPN4). Whereas the small subunit is identical for both enzymes, the large subunits share 55-65% sequence homology [4,12]. The μ-and m-calpains differ in their requirements of intracellular Ca 2+ and require for their activity the presence of micromolar and millimolar Ca 2+ concentrations, respectively.The word "calpain" was originally used for classical μ-and mcalpains, but because 80K itself is fully active, the word "calpain" is now used for 80K as well [13]. The 80K and 30K contain four (I-IV) and two (V and VI) domains, respectively [14] (Figure 1). The N-terminal region of domain I of the large subunit is autolyzed upon activation by Ca 2+ . This autoproteolysis seems to be required for full protease activity, and reduces ...

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

Cited by 5 publications

References 20 publications

Epigenetic revival of a dead cardiomyocyte through mitochondrial interventions

Epigenetic revival of a dead cardiomyocyte through mitochondrial interventions

Proteolytic degradation of atrial sarcomere proteins underlies contractile defects in atrial fibrillation

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

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