Calpain inhibition reduces infarct size and improves global hemodynamics and left ventricular contractility in a porcine myocardial ischemia/reperfusion model

Khalil, Philipe N.; Neuhof, Christiane; Huss, Ralf; Pollhammer, M.; Khalil, Maurice N.; Neuhof, H.; Fritz, Hans; Siebeck, Matthias

doi:10.1016/j.ejphar.2005.10.032

Cited by 78 publications

(53 citation statements)

References 34 publications

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“…Additionally, the activation of calpains has been identified in several types of cardiovascular diseases, including aortic aneurysm and diabetic cardiomyopathy (17,18). Furthermore, inhibition of calpains by treatment with a pharmacological inhibitor or overexpression of calpastatin may protect the heart from ischemiareperfusion injury (19)(20)(21). The present study further demonstrated that expression of μ-and m-calpain significantly increased with the progression of heart failure, indicating that calpains are implicated in the ventricular remodelling in valvular heart disease caused by CHF.…”

Section: Discussionsupporting

confidence: 58%

Increased expression of calpain and elevated activity of calcineurin in the myocardium of patients with congestive heart failure

Yang

Ma²,

Tan³

et al. 2010

Int J Mol Med

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Abstract. The angiotensin (Ang) II/Ang II receptor (ATR)-associated calcium signaling pathway is the major cause of ventricular remodelling in patients with congestive heart failure (CHF). However, the calcium-regulated proteinases responsible for Ang II-induced remodelling are not well understood. We investigated the profiles of the Ang II/ ATR/calpain/calcineurin (CaN) pathway in human failing heart. We measured both the plasma and cardiac levels of Ang II and cardiac mRNA expression of ATR in 39 patients with CHF and 38 healthy controls. Importantly, protein expression of calpains, cleavage of cain/cabin1 and activity of CaN were tested. Both plasma and cardiac levels of Ang II were significantly increased in patients with CHF (both p<0.01), and the plasma Ang II concentration was closely correlated with the parameters of ventricular remodelling (r=±0.29-0.65, p<0.05 or <0.01). In addition, the cardiac level of AT1R but not AT2R was significantly upregulated in mild failing hearts (p<0.05) but dramatically downregulated in severe failing ones (p<0.01). CHF was associated with a marked upregulation of calpains, an increased cleavage of cain/cabin1, and the activation of CaN in the failing ventricular tissue. In patients with CHF, calpain upregulation was associated with an increase in cleavage of cain/cabin1 and the activation of CaN, indicating that these changes in calciumregulated proteinases contribute to Ang II-induced cardiac remodelling.

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Section: Discussionsupporting

confidence: 58%

Increased expression of calpain and elevated activity of calcineurin in the myocardium of patients with congestive heart failure

Yang

Ma²,

Tan³

et al. 2010

Int J Mol Med

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“…Calpain has been implicated in post-MI myocardial injury (11)(12)(13). The present study employed cardiomyocyte-specific Capn4 knock-out mice to investigate the role of calpain-1 and calpain-2 in LV remodeling and myocardial dysfunction following MI.…”

Section: Discussionmentioning

confidence: 99%

“…Calpain activity is increased in the infarcted heart and in myocardia of patients with heart failure (9,10). Pharmacologic inhibition of calpain reduces ischemic cardiac injury and preserves cardiac structure after acute MI (11)(12)(13)(14). A recent study showed that calpain-1 knock-out reduced whereas calpain-1 overexpression enhanced myocardial injury and dysfunction within 4 days after coronary occlusion (15).…”

Section: Myocardial Infarction (Mi)mentioning

confidence: 99%

Deficiency of Capn4 Gene Inhibits Nuclear Factor-κB (NF-κB) Protein Signaling/Inflammation and Reduces Remodeling after Myocardial Infarction

Wei²,

Wang

et al. 2012

Journal of Biological Chemistry

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Background:The causal role of calpain in myocardial remodeling after infarction has not been addressed. Results: Deficiency of Capn4 inhibited NF-B signaling and inflammation and reduced myocardial remodeling, dysfunction, and mortality after infarction. Conclusion: Calpain contributes to myocardial inflammation and remodeling after infarction. Significance: This study provides a significant insight into the function of calpain in post-myocardial infarction remodeling.

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“…Examples of compounds that may work through distal inhibition include calpain antagonists 178 and polymers that seal plasma membranes. 179 …”

Section: Potential Therapeutic Opportunitiesmentioning

confidence: 99%

Programmed Necrosis, Not Apoptosis, in the Heart

Kung

Konstantinidis

Kitsis

2011

Circulation Research

253

208

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Abstract:It is well known that apoptosis is an actively mediated cell suicide process. In contrast, necrosis, a morphologically distinct form of cell death, has traditionally been regarded as passive and unregulated. Over the past decade, however, experiments in Caenorhabditis elegans and mammalian cells have revealed that a significant proportion of necrotic death is, in fact, actively mediated by the doomed cell. Although a comprehensive understanding of necrosis is still lacking, some key molecular events have come into focus. Cardiac myocyte apoptosis and necrosis are prominent features of the major cardiac syndromes. Accordingly, the recognition of necrosis as a regulated process mandates a reexamination of cell death in the heart. This review discusses pathways that mediate programmed necrosis, how they intersect with apoptotic pathways, roles of necrosis in heart disease, and new therapeutic opportunities that the regulated nature of necrosis presents. (Circ Res. 2011;108:1017-1036.) Key Words: cell death Ⅲ necrosis Ⅲ apoptosis Ⅲ myocardial infarction Ⅲ heart failure A s recently as 30 years ago, cell death was viewed as a passive and unregulated process. Irreversible cellular injury (from physical/chemical/biological insults) was thought to kill solely by overwhelming cellular homeostasis. In this model, the cell was merely the recipient of damage and not a participant in its own demise. Unexplained by this paradigm, however, were the highly reproducible deaths of specific cells during the development of multiple organisms. In fact, these developmental cell deaths (termed "programmed cell death") had long been recognized but remained poorly understood. Studies in Caenorhabditis elegans showed that a relatively small network of genes (ced-9-|ced-43ced-3) regulates the deletion of a specific 131 cells during development. 1,2 These experiments provided the first evidence that any form of cell death was actively mediated. Subsequent work demonstrated that these genes had been conserved for more than 600 million years of evolution to humans. The orthologs of ced-9, ced-4, and ced-3 are, respectively, the bcl-2 (B-cell lymphoma 2) family, apaf-1 (apoptotic protease activating factor-1), and the caspase family. 3 Moreover, not only do these genes regulate developmental cell deaths in mammals, they also control the deaths of postnatal cells by a specific process termed apoptosis (discussed below). Taken together, these observations establish that cells often die through active mechanisms that have been highly conserved through evolution.Research more than the past 2 decades has built on these observations to produce a relatively mature understanding of the pathways that mediate apoptosis. These include an intrinsic pathway, which is conserved back to C elegans, that uses mitochondria and endoplasmic reticulum; and an extrinsic pathway that involves cell surface death receptors. These pathways are critical in the regulation of apoptosis. 3 Apoptosis is characterized by cell shrinkage and fragmentation into membra...

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Calpain inhibition reduces infarct size and improves global hemodynamics and left ventricular contractility in a porcine myocardial ischemia/reperfusion model

Cited by 78 publications

References 34 publications

Increased expression of calpain and elevated activity of calcineurin in the myocardium of patients with congestive heart failure

Increased expression of calpain and elevated activity of calcineurin in the myocardium of patients with congestive heart failure

Deficiency of Capn4 Gene Inhibits Nuclear Factor-κB (NF-κB) Protein Signaling/Inflammation and Reduces Remodeling after Myocardial Infarction

Programmed Necrosis, Not Apoptosis, in the Heart

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