Novel Role for Caspase-Activated DNase in the Regulation of Pathological Cardiac Hypertrophy

Abstract

Abstract-Caspase-activated DNase (CAD) is a double-strand-specific endonuclease that is responsible for the cleavage of nucleosomal spacer regions and subsequent chromatin condensation during apoptosis. Given that several endonucleases (eg, DNase I, DNase II, and Endog) have been shown to regulate pathological cardiac hypertrophy, we questioned whether CAD, which is critical for the induction of DNA fragmentation, plays a pivotal role in pressure overload-elicited cardiac hypertrophy. A CAD-knockout mouse model was generated and subjected to aortic banding for 8 weeks. The extent of cardiac hypertrophy was evaluated by echocardiography and pathological and molecular analyses. Our results demonstrated that the disruption of CAD attenuated pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Conversely, transgenic mice with cardiac-specific overexpression of CAD showed an aggravated cardiac hypertrophic response to chronic pressure overload. Mechanistically, we discovered that the expression and activation of mitogen-activated protein kinase-extracellular signal-regulated kinase 1/2 was significantly reduced in the CADknockout hearts compared with the control hearts; however, they were greatly increased in the CAD-overexpressing hearts after aortic banding. Similar results were observed in ex vivo cultured neonatal rat cardiomyocytes after treatment with angiotensin II for 48 hours. These data indicate that CAD functions as a necessary modulator of the hypertrophic response by regulating the mitogen-activated protein kinase-extracellular signal-regulated kinase 1/2 signaling pathway in the heart. Our study suggests that CAD might be a novel target for the treatment of pathological cardiac hypertrophy and heart failure. (Hypertension. 2015;65:871-881.

Growth Arrest–Specific 6 Exacerbates Pressure Overload–Induced Cardiac Hypertrophy

“…Moreover, intravenous administration might be more efficient to inhibit GAS6 rather than MEK1/2 and ERK1/2 because of their different distribution (plasma versus cytoplasm). Second, experiments from animal model indicated that ERK1/2 deficiency in murine hearts led to deteriorative cardiac function under physiological condition, 35 whereas, in the present study, we observed normal cardiac morphology and function in GAS6-KO mice (Figure 3) without stimuli. Hence, in terms of hearts, it seems that GAS6 inhibition is safer than ERK1/2 inhibition.…”

“…In consistent with this hypothesis, some recent studies have demonstrated that an excessive activation of ERK1/2 leads to more severe cardiac hypertrophy and function. 35,36 Notably, many studies have indicated that Axl/ GAS6 binding can exert biological functions via the activation of MEK1/2-ERK1/2 signaling. Goruppi et al 37 demonstrated that GAS6 has mitogenic and prosurvival activities in NIH3T3 fibroblasts, and the activity is dependent on the activation of ERK1/2.…”

Procaine Induces Epigenetic Changes in HCT116 Colon Cancer Cells

“…One of these mechanisms postulates that demethylating agent such as procaine could activate tumor suppressor gene(s), which, in turn, enforce the cells to commit apoptosis [36, 37]. Other mechanisms suggest the activation of caspase-activated DNase (CAD), which degrades DNA after a cascade of activation processes [38]. In the present investigation all drug combinations applied to HCT116 colon cancer cells have resulted in a degradation pattern that might indicate the occurrence of drugs-induced apoptosis [27, 39, 40].…”

Hyperoside Protects Against Pressure Overload-Induced Cardiac Remodeling via the AKT Signaling Pathway

“…Cardiac fibrosis is a major feature of hypertrophic cardiomyopathy and contributes to ventricular dysfunction and life-threatening arrhythmia [13,24]. Our in vivo study showed that Hyp treatment reduced the pressure overload-induced fibrotic response.…”