When the heart is exposed to OxS or hypertrophic stimuli, JNK is activated via MKK4/7 (mitogen-activated protein kinase kinase 4 and 7) and regulates multiple downstream proteins, including Bcl family proteins, thus, enhancing apoptosis and connexin-43, thus, regulating gap junctions and extracellular matrix proteins, thus, regulating cardiac fibrosis and mitochondrial JNK, thus, regulating mitochondrial function, and by all these mechanisms, the JNK pathway is complexly involved in the development of cardiac hypertrophy (for review see: [131,132]). This evidence concerns the gene MAP2K4 and fibrosis.