University of Manchester
Ruiz Velasco hernandez, Andrea.
ERK5 as a metabolic regulator in the heart.
Degree: 2020, University of Manchester
Approximately 18 million people die of
cardiovascular disease (CVD) around the world each year, making
CVDs the number one cause of death in the world1. The extracellular
signal-regulated protein kinase 5 (ERK5) has been found to play an
essential role in cell growth and survival in heart disease,
however, its role in other cell functions is still under
investigation. Therefore, the objective of this study was to
uncover the potential participation of ERK5 in cardiac metabolism,
particularly under pathological conditions. In the setting of
high-fat diet (HFD)-induced obesity, it was demonstrated that ERK5
regulates peroxisome proliferator-activated receptor gamma
co-activator alpha (PGC1alpha) expression through myocyte enhancer
factor 2 a (MEF2A) and MEF2D, this way maintaining mitochondrial
biogenesis, fatty acid oxidation (FAO), and oxidative stress
control. Mimicking HFD stress, saturated fatty acid treatment in
adult rat cardiomyocytes (ARCMs) showed that the oxidative stress
produced by GP91PHOX activates calpain1, which degrades ERK5.
Preventing ERK5 loss by Gp91phox or Calpain- 1 inhibition preserved
mitochondrial function and FAO. Similarly, restoring ERK5
expression in ERK5-deficient hearts using adeno-associated virus 9
(AAV9) prevented the development of heart failure after HFD
feeding. In the context of myocardial infarction (MI), it was
established that ERK5 loss leads to a dampened cardiac insulin
response, increased apoptosis and accelerated cardiac dysfunction
through an increased inhibition of the insulin receptor substrate 1
(IRS1) by miR128-3p. Subjecting ARCMs and human-induced pluripotent
stem cell-derived cardiomyocytes (iPSC-CMs) to hypoxia, it was
discovered that ERK5 regulates miR128-3p by activation of the CAMP
responsive element binding protein (CREB)-CCAAT/enhancer-binding
protein beta (CEBPbeta) pathway. Consistent with these
observations, ERK5 restoration, CEBPbeta overexpression, or
miR128-3p inhibition in ERK5-deficient mice by AAV9 injection
normalized IRS1 level and cardiac function after MI. These results
indicate that the ERK5-CEBPbeta pathway is essential for the
prevention of insulin resistance after an ischaemic insult by
protecting IRS1. ERK5 was found to be a cardioprotective regulator
of lipid and glucose metabolism under stress; therefore, indicating
its potential as a treatment to prevent heart
Advisors/Committee Members: LIU, VICKY W, Wang, Joy, Liu, Vicky.
Subjects/Keywords: ERK5; Metabolic cardiomyopathy; Myocardial infarction; Cellular signalling; MicroRNA; Kinases; Obesity; Cardiovascular disease; Hypoxia
to Zotero / EndNote / Reference
APA (6th Edition):
Ruiz Velasco hernandez, A. (2020). ERK5 as a metabolic regulator in the heart. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:323374
Chicago Manual of Style (16th Edition):
Ruiz Velasco hernandez, Andrea. “ERK5 as a metabolic regulator in the heart.” 2020. Doctoral Dissertation, University of Manchester. Accessed February 28, 2020.
MLA Handbook (7th Edition):
Ruiz Velasco hernandez, Andrea. “ERK5 as a metabolic regulator in the heart.” 2020. Web. 28 Feb 2020.
Ruiz Velasco hernandez A. ERK5 as a metabolic regulator in the heart. [Internet] [Doctoral dissertation]. University of Manchester; 2020. [cited 2020 Feb 28].
Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:323374.
Council of Science Editors:
Ruiz Velasco hernandez A. ERK5 as a metabolic regulator in the heart. [Doctoral Dissertation]. University of Manchester; 2020. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:323374