MAP4 as a New Candidate in Cardiovascular Disease

Abstract

Microtubule and mitochondrial dysfunction have been implicated in the pathogenesis of cardiovascular diseases (CVDs), including cardiac hypertrophy, fibrosis, heart failure, and hypoxic/ischemic related heart dysfunction. Microtubule dynamics instability leads to disrupted cell homeostasis and cell shape, decreased cell survival, and aberrant cell division and cell cycle, while mitochondrial dysfunction contributes to abnormal metabolism and calcium flux, increased cell death, oxidative stress, and inflammation, both of which causing cell and tissue dysfunction followed by CVDs. A cytosolic skeleton protein, microtubule-associated protein 4 (MAP4), belonging to the family of microtubule-associated proteins (MAPs), is widely expressed in non-neural cells and possesses an important role in microtubule dynamics. Increased MAP4 phosphorylation results in microtubule instability. In addition, MAP4 also expresses in mitochondria and reveals a crucial role in maintaining mitochondrial homeostasis. Phosphorylated MAP4 promotes mitochondrial apoptosis, followed by cardiac injury. The aim of the present review is to highlight the novel role of MAP4 as a potential candidate in multiple cardiovascular pathologies.

Keywords: cardiovascular disease; microtubule; microtubule-associated protein 4; microtubule-associated proteins; mitochondria.

FIGURE 1

Schematic illustrating the role of MAP4 in CVD. Inflammation, hypoxia, ischemia, etc., stimulate the activation of the MKK6/p38 MAPK pathway. The activated p38 MAPK induces MAP4 phosphorylation and, sequentially, the depolymerization of MT. The phosphorylated MAP4 detaches from MT and translocates to mitochondria from cytosol, leading to mitochondrial permeability transition pore (mPTP) opening and cytochrome c (cyt-c) release, which activates caspase pathway and promotes mitochondrial apoptosis. Increased apoptosis together with MT depolymerization causes cardiomyocyte/endothelial cell dysfunction, which is involved in the pathogenesis of CVD.