A Role for Caspase-1 in Heart Failure

Abstract

Abstract-Apoptosis of cardiomyocytes is increased in heart failure and has been implicated in disease progression. The activation of "proapoptotic" caspases represents a key step in cardiomyocyte apoptosis. In contrast, the role of "proinflammatory" caspases (caspases 1, 4, 5, 11, 12) is unclear. Here, we study the cardiac function of caspase-1. Gene array analysis in a murine heart failure model showed upregulation of myocardial caspase-1. In addition, we found increased expression of caspase-1 protein in murine and human heart failure. Mice with cardiomyocyte-specific overexpression of caspase-1 developed heart failure in the absence of detectable formation of interleukin (IL)-1␤ or IL-18 and inflammation. Transgenic caspase-1 induced primary cardiomyocyte apoptosis before structural and molecular signs of myocardial remodeling occurred. In contrast, deletion of endogenous caspase-1 was beneficial in the setting of myocardial infarction-induced heart failure. Furthermore, caspase-1-deficient mice were protected from ischemia/reperfusion-induced cardiomyocyte apoptosis. Studies in primary rat cardiomyocytes indicated that caspase-1 induces cardiomyocyte apoptosis primarily through activation of caspases-3 and -9. In contrast to previous findings, which imply a proinflammatory role of caspase-1, these data suggest a primary proapoptotic role for caspase-1 in cardiomyocytes. Our findings support a functional role for caspase-1-mediated myocardial apoptosis contributing to the progression of heart failure. (Circ Res. 2007;100:645-653.)

The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse

“…Caspase-1 activity is increased in the myocardium minutes after the onset of ischemia, remains elevated for several days, and leads to cardiomyocyte death (10)(11)(12). Herein we confirm the presence of cryopyrin inflammasomes in leukocytes, endothelial cells, and fibroblasts in the granulation tissue early during the infarct period and describe formation of active cryopyrin inflammasomes in cardiomyocytes bordering the infarct zone later during the infarct process.…”

“…Overexpression of caspase-1 caused cell death in cultured cardiomyocytes, whereas deletion of endogenous caspase-1 was previously shown to protect against ischemia/reperfusion-induced death (10)(11)(12). Accordingly, mice overexpressing caspase-1 had larger areas of ischemic damage, more severe cardiac enlargement, and a reduced survival after AMI; whereas caspase-1-deficient mice were protected after AMI (10)(11)(12).…”

“…Caspase-1 is a key modulator of the inflammatory response to tissue injury and participates both in the amplification of the inflammatory response and also in the promotion of cell death (7)(8)(9). Experimental studies in mice with genetic deletion of caspase-1 have identified caspase-1 inhibition as a potential target for pharmacologic intervention in the setting of AMI (10)(11)(12). A recent report described formation of the inflammasome in a mouse model of ischemia/reperfusion and reports that ASC knockout mice were protected (13).…”

Inflammasome: a new villain in heart disease

“…The protective effect of ASC gene deletion was not seen, however, in a model of global ischemia-reperfusion in the explanted heart ex vivo [27], raising the question of whether ASC expression in the leukocytes in the blood is more important than ASC expression in the heart [29]. The knowledge of the role of caspase-1 in myocardial ischemic injury precedes the knowledge of caspase-1 being part of the inflammasome, and data consistently show that caspase-1 KO mice are protected from myocardial ischemic injury [25,30] Deleting the caspase-1 coding gene is enough to ameliorate post-infarction heart failure [31], and mice lacking caspase-1 exhibited both improved peri-infarct survival and a decreased rate of ventricular dilatation [30]. Altogether these data show that disruption of one of the components of the inflammasome is sufficient to prevent its activation and this inhibition provides a beneficial impact on cardiac injury and remodeling.…”

Sterile Inflammation and Degradation Systems in Heart Failure

“…7, 28 The NLRP3 inflammasome effector, caspase-1, is upregulated in murine and human failing hearts. 29 Genetic ablation of Nlrp3 in cardiac-specific calcineurin transgenic mice, which exhibit dilated cardiomyopathy, reduces proinflammatory cytokine maturation and cardiac inflammation, and improves systolic performance. 30 agy was initially believed to be a non-selective process, but recent studies have described the process of selective autophagy, including selective mitochondrial autophagy, known as mitophagy.…”