Cellular FLICE-Inhibitory Protein Protects Against Cardiac Remodeling Induced by Angiotensin II in Mice

Abstract

Abstract-The development of cardiac hypertrophy in response to increased hemodynamic load and neurohormonal stress is initially a compensatory response that may eventually lead to ventricular dilatation and heart failure. Cellular FLICE-inhibitory protein (cFLIP) is a homologue of caspase 8 without caspase activity that inhibits apoptosis initiated by death receptor signaling. Previous studies showed that cFLIP expression was markedly decreased in the ventricular myocardium of patients with end-stage heart failure. However, the critical role of cFLIP on cardiac remodeling remains unclear. To specifically determine the role of cFLIP in pathological cardiac remodeling, we used heterozygote cFLIP ϩ/Ϫ mice and transgenic mice with cardiac-specific overexpression of the human cFLIP L gene. Our results demonstrated that the cFLIP ϩ/Ϫ mice were susceptible to cardiac hypertrophy and fibrosis through inhibition of mitogen-activated protein kinase kinase-extracellular signal-regulated kinase 1/2 signaling, whereas the transgenic mice displayed the opposite phenotype in response to angiotensin II stimulation. These studies indicate that cFLIP protein is a crucial component of the signaling pathway involved in cardiac remodeling and heart failure.

Caspase Recruitment Domain 6 Protects Against Cardiac Hypertrophy in Response to Pressure Overload

“…36 Moreover, pharmacological inhibition of the MEK-ERK1/2 and JNK1/2 signaling pathways could have a beneficial effect on cardiac function by acting directly to decrease the proliferation of myocardial fibroblasts. 17,37,38 Thus, in the current study, the blockade of MEK-ERK1/2 and JNK1/2 signaling as a consequence of CARD6 overexpression likely contributed, at least in part, to reduce the degree of cardiac fibrosis observed in response to pressure overload.…”

“…To elucidate these possible mechanisms, we next investigated the expression and activity of mitogen-activated protein kinase (MAPK) signaling molecules (ie, MEK1/2, ERK1/2, JNK1/2, and P38), as the MAPK pathway is known to play a crucial role in pathological cardiac hypertrophy. 17 The expression levels of phosphorylated MEK1/2, ERK1/2, and JNK1/2 were greatly increased in cCARD6-KO hearts compared with CARD6-Flox hearts after 4 weeks of AB ( Figure 5A). In contrast, CARD6 overexpression reduced AB-triggered activation of MEK1/2, ERK1/2, and JNK1/2, as evidenced by remarkably decreased phosphorylation of MEK1/2, ERK1/2, and JNK1/2 in transgenic hearts relative to control hearts ( Figure 5B).…”

Interferon Regulatory Factor 9 Protects Against Cardiac Hypertrophy by Targeting Myocardin

“…An expanded Methods section is available in the online-only Data Supplement, including Reagents, Animal Models and Procedures, 3,[14][15][16][17] Echocardiography and Hemodynamic Measurements, 14,18,19 Histological Analysis, Cultured NRCMs and Recombinant Adenoviral Vectors, 14,16 Immunofluorescence Analysis, Western Blotting, and Quantitative Real-Time PCR, Plasmid Constructs, 13 Immunoprecipitation and the GST Pull-down Assay, Luciferase Reporter Assays, 20 EMSA, 17,21,22 and Statistical Analysis.…”

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

“…149,150 In response to pathological stimuli, continuous pathogenic signals may cause the development of compensatory hypertrophy to a maladaptive level, together with a reduction in cardiac output and a dramatic elevation of the risk of heart failure, arrhythmia, and sudden death. 151 The mechanical load and humoral factors, eg, angiotensin II (Ang II), endothelin-1, and norepinephrine, are the most common inductors of pathological cardiac hypertrophy, which is always accompanied by hypertension. [152][153][154] The orchestrated signal transduction events recognize injurious stimuli, induce the structural and functional changes in regulators, and ultimately reactivate fetal gene, promote protein synthesis, and increase cell size.…”