Inhibition of Extracellular Signal–Regulated Kinase Enhances Ischemia/Reoxygenation–Induced Apoptosis in Cultured Cardiac Myocytes and Exaggerates Reperfusion Injury in Isolated Perfused Heart

Abstract

Abstract-Three major mammalian mitogen-activated protein kinases, extracellular signal-regulated kinase (ERK), p38, and c-Jun NH 2 -terminal protein kinase (JNK), have been identified in the cardiomyocyte, but their respective roles in the heart are not well understood. The present study explored their functions and cross talk in ischemia/reoxygenation (I/R)-induced cardiac apoptosis. Exposing rat neonatal cardiomyocytes to ischemia resulted in a rapid and transient activation of ERK, p38, and JNK. On reoxygenation, further activation of all 3 mitogen-activated protein kinases was noted; peak activities increased (fold) by 5.5, 5.2, and 6.2, respectively. Visual inspection of myocytes exposed to I/R identified 18.6% of the cells as showing morphological features of apoptosis, which was further confirmed by DNA ladder and terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling (TUNEL). Myocytes treated with PD98059, a MAPK/ERK kinase (MEK1/MEK2) inhibitor, displayed a suppression of I/R-induced ERK activation, whereas p38 and JNK activities were increased by 70.3% and 55.0%, respectively. In addition, the number of apoptotic cells was increased to 33.4%. With pretreatment of cells with SB242719, a selective p38 inhibitor, or SB203580, a p38 and JNK2 inhibitor, I/RϩPD98059-induced apoptotic cells were reduced by 42.8% and 63.3%, respectively. Hearts isolated from rats treated with PD98059 and subjected to global ischemia (30 minutes)/reoxygenation (1 hour) showed a diminished functional recovery compared with the vehicle group. Coadministration of SB203580 attenuated the detrimental effects of PD98059 and significantly improved cardiac functional recovery. The data taken together suggest that ERK plays a protective role, whereas p38 and JNK mediate apoptosis in cardiomyocytes subjected to I/R, and the dynamic balance of their activities is critical in determining cardiomyocyte fate subsequent to reperfusional injury. (Circ Res. 2000;86:692-699.)

Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic

“…Inhibition of ERK activation was shown to exaggerate cardiac injury. 32 In agreement with that observation, increased ERK activation in treated animals accompanied improved heart morphology. The activation of both ERK and JNK pathways are thought to protect cardiomyocytes from apoptosis, although the role of p38 remains unclear.…”

Interference with ERK Thr188 phosphorylation impairs pathological but not physiological cardiac hypertrophy

“…However, many mouse models point toward a pivotal role of ERK1/2 in the prevention of apoptotic cell death: cell death is significantly increased in mice with cardiac overexpression of dominant-negative Raf1, in mice treated with MEK1/2-inhibitors, and in ERK1 −/− ERK2 +/− mice (11,12,36), whereas overexpression of constitutively active MEK1 increases cell survival (37,38). Therefore, inhibition of , and quantification of interstitial fibrosis of ventricular myocardium (E) of WT mice and transgenic mice with cardiac expression of wild-type ERK2 T188T (T188T) or phosphorylation-deficient ERK2 T188A (T188A) at the age of 8 wk (CON), at the age of 9 mo (9 MON), and afterERK1/2 activity is detrimental for the heart and, thus, cannot be used to target cardiac hypertrophy.…”

Cardiogenic Shock and Respiratory Failure in a Patient With Metastatic Melanoma Receiving Trametinib Therapy

“…Cardiomyopathy has also been observed with other MEK1/2 inhibitors such as binimetinib and cobimetinib, suggesting a class effect.The use of the MEK1/2 inhibitor PD98059 has been shown to impair organization of the sarcomere in the setting of a 1 -adrenergic agonists [3]. MEK1/2 inhibition in cultured rat cardiomyocytes has also been shown to increased ischemia/ reoxygenation-induced apoptosis [4]. It is also notable that MEK inhibitors have been associated with skeletal muscle weakness, such as in dropped head syndrome, a focal myopathy of the neck extensor muscles that can develop from the effects of inhibiting MEK1/2 on fatty acid uptake by skeletal muscles [5,6].…”