Crosstalk between mitogen-activated protein kinases and mitochondria in cardiac diseases: therapeutic perspectives

Abstract

Cardiovascular diseases cause more mortality and morbidity worldwide than any other diseases. Although many intracellular signaling pathways influence cardiac physiology and pathology, the mitogen-activated protein kinase (MAPK) family has garnered significant attention because of its vast implications in signaling and crosstalk with other signaling networks. The extensively studied MAPKs ERK1/2, p38, JNK, and ERK5, demonstrate unique intracellular signaling mechanisms, responding to a myriad of mitogens and stressors and influencing the signaling of cardiac development, metabolism, performance, and pathogenesis. Definitive relationships between MAPK signaling and cardiac dysfunction remain elusive, despite 30 years of extensive clinical studies and basic research of various animal/cell models, severities of stress, and types of stimuli. Still, several studies have proven the importance of MAPK crosstalk with mitochondria, powerhouses of the cell that provide over 80% of ATP for normal cardiomyocyte function and play a crucial role in cell death. Although many questions remain unanswered, there exists enough evidence to consider the possibility of targeting MAPK-mitochondria interactions in the prevention and treatment of heart disease. The goal of this review is to integrate previous studies into a discussion of MAPKs and MAPK-mitochondria signaling in cardiac diseases, such as myocardial infarction (ischemia), hypertrophy and heart failure. A comprehensive understanding of relevant molecular mechanisms, as well as challenges for studies in this area, will facilitate the development of new pharmacological agents and genetic manipulations for therapy of cardiovascular diseases.

Keywords: Cardiac diseases; Cell signaling; Heart; MAPK; Mitochondria.

Figure 1

Main MAPK signaling pathways in the heart.

Figure 2

Major downstream targets of ERK1/2 MAPK in response to oxidative stress and growth stimuli in the heart.

Figure 3

p38-induced stimulation of death signaling pathways in response to oxidative stress and hypertrophic stimuli.

Figure 4

Major downstream targets of JNK MAPK in response to oxidative stress and growth stimuli in the heart.

Figure 5

Proposed role of ERK5 MAPK during oxidative stress and cardiac hypertrophy.

Figure 6

Bidirectional interactions between MAPKs and mitochondria.