Targeted Activation of c-Jun N-terminal Kinase in Vivo Induces Restrictive Cardiomyopathy and Conduction Defects

Abstract

The stress-activated protein kinase, c-Jun N-terminal kinase (JNK), has been implicated in the process of cardiac hypertrophy and apoptosis, yet the specific roles of JNK in heart failure are unclear. To determine the effects of JNK activation in intact heart, we established transgenic animals using a Cre/loxP-mediated gene switch approach to achieve targeted expression of an upstream activator, mitogen-activated protein kinase kinase 7 (D) (MKK7D), in ventricular myocytes. MKK7D expression led to significant JNK activation, robust induction of the fetal gene program, and contractile dysfunction. The animals died ϳ7 weeks after birth with signs of congestive heart failure. Doppler mode echocardiography revealed a marked stiffening of JNK-activated hearts that was associated with the remodeling of specific extracellular matrix components. Gene expression analysis of MKK7D hearts revealed up-regulation of transforming growth factor ␤ signaling, offering a potential molecular mechanism underlying changes in extracellular matrix composition. In addition, we demonstrated that JNK activation led to specific loss of connexin 43 protein and gap junctions without affecting the expression or localization of other key intercalated disc proteins. This specific and localized gap junction remodeling resulted in significant slowing of ventricular electrical conduction in JNK-activated hearts. These results represent the first characterization of JNK-mediated cardiac pathology in vivo and support an important role for JNK signaling in specific aspects of cardiac remodeling in the pathogenesis of cardiac disease.

Cdc42 is an antihypertrophic molecular switch in the mouse heart

“…This increase in cardiac hypertrophy associated with p38 or JNK inhibition was reversed by deletion of calcineurin Aβ, showing that calcineurin-NFAT signaling was a mechanism whereby these kinases mediated their antihypertrophic effect. That JNK and p38 can have an antihypertrophic effect is also somewhat consistent with the phenotype of mice with MKK3/6 or MKK7 overexpression in the heart, which showed severe cardiac dilation and failure without prominent hypertrophy (39,40). We also previously showed that Jnk1 +/-Jnk2 -/-mice developed spontaneous cardiac hypertrophy with aging and that young mice subjected to TAC had a greater hypertrophic response (27).…”

Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease

“…The effects of Lmna mutations on proteins particularly important for conduction system structure or function might weaken these specialized cells and promote early apoptotic death. Activation of c-jun N-terminal kinase (JNK), a stress-activated protein kinase, has been previously implicated in the process of cardiomyopathy and cardiac conduction system disease by downregulation of the gap junction protein connexin 43 [32,33], and cardiomyocyte apoptosis [34]. However, the present study showed no c-Jun activation in hearts from Lmna +/-mice.…”

“…Activation of MAPK signaling cascade has recently been identified in hearts from mice homozygous for the LMNA mutation H222P [23], and this molecular pathway has previously been implicated in the development of cardiomyopathy, conduction defects [32,33] and apoptosis [34].…”

Mitogen-Activated Protein Kinases in Heart Development and Diseases

“…80 However, in vivo JNK activation in transgenic animal models failed to induce cardiac hypertrophy. [81][82][83][84] Rather, the transgenic animals developed lethal restrictive cardiomyopathy with no myocyte hypertrophy but a significant induction of fetal gene expression. However, the direct impact (at the earliest time point) of JNK activation on cardiac gene expression and function remains unclear and should be studied by achieving inducible JNK activation in the adult heart as reported.…”