JNK and cardiometabolic dysfunction

Abstract

Cardiometabolic syndrome (CMS) describes the cluster of metabolic and cardiovascular diseases that are generally characterized by impaired glucose tolerance, intra-abdominal adiposity, dyslipidemia, and hypertension. CMS currently affects more than 25% of the world's population and the rates of diseases are rapidly rising. These CMS conditions represent critical risk factors for cardiovascular diseases including atherosclerosis, heart failure, myocardial infarction, and peripheral artery disease (PAD). Therefore, it is imperative to elucidate the underlying signaling involved in disease onset and progression. The c-Jun N-terminal Kinases (JNKs) are a family of stress signaling kinases that have been recently indicated in CMS. The purpose of this review is to examine the in vivo implications of JNK as a potential therapeutic target for CMS. As the constellation of diseases associated with CMS are complex and involve multiple tissues and environmental triggers, carefully examining what is known about the JNK pathway will be important for specificity in treatment strategies.

Keywords: Signaling; cardiovascular disease; metabolic regulation.

Figure 1. JNK pathway

A schematic representation of the JNK pathway. (A) The JNK pathway can be activated by many stimuli, including UV, reactive oxygen species (ROS), growth factors, inflammatory cytokines, and a wide spectrum of cellular stresses. These stress signals then orchestrate the binding of multiple JNK-related proteins to scaffolding proteins (JIP1-2, POSH, Arrestin2-3). Upstream kinases phosphorylate and activate JNK which then phosphorylates different downstream targets, including protein kinases, cytosolic substrates, and transcription factors, leading to biological responses. (B) The JNK pathway can be activated by many stimuli, specificity comes from the selective activation of MAP3K activation by individual stimulus. Upstream kinases MLKs, ASKs, and TAK1 are activated mainly by high-fat diet (HFD), oxidative stresses, and cytokines, respectively. Abbreviations: ASK, apoptosis signal-regulating kinase; JIP, JNK-interacting protein; MLK, mixed lineage kinase; POSH, Plenty of SH3.

Figure 2. JNK controls insulin signaling

JNK activation in the liver suppresses Fgf21 production, therefore reducing Fgf21 action on its target tissues, including liver, muscle, and adipose tissue, thus leading to insulin resistance. JNK activation also attenuates insulin signaling via increased Il6 production in adipose tissue, which then promotes IRS1 protein degradation in liver.

Figure 3. Role of JNK in atherosclerosis

(A) JNK1 promotes apoptosis in endothelium after chronic inflammation and promotes atherosclerosis. (B) Similar to endothelium, JNK1 in bone marrow-derived immune cells (including monocytes) also promotes apoptosis after chronic inflammation which leads to less atherosclerosis in mice. (C) On the other hand, JNK2 knockout mice were protected from atherosclerosis through reduced number of foam cell formation as internalization of scavenger receptor A and lipid accumulation without phosphorylation of receptor are severely decreased.

Figure 4. Proposed mechanisms through which JNK signaling promotes divergent hypertrophic phenotypes

(A) Extracellular signals activate separate upstream MAP3Ks and JNK activators, leading to activation of MAP2Ks MKK4 and MKK7. Depending on localization of MAP2K, mediated by specific scaffolding proteins, JNK phosphorylates anti- or pro-hypertrophic signaling pathways. (B) JNK can play direct or indirect role in LV hypertrophy and heart failure.

Figure 5. JNK in cardiometabolic diseases

A schematic diagram explains the JNK connects the metabolic diseases to cardiovascular disease.