Regulatory role of p38y and p38d in inflammation and cardiovascular system in homeostasis and disease

Resumo

ABSTRACT IN ENGLISH Cells recognize and respond to extracellular stimuli by engaging different intracellular programs, such as the signaling cascade that leads to the activation of the mitogen activated protein kinases (MAPKs). All eukaryotic cells posses multiple MAPK pathways, which regulate a diverse array of cellular processes. In mammals four distinct subgroups have been described (1) extracellular signal-regulated kinases 1/2 (ERKs), (2) c-jun N-terminal or stress-activated protein kinases (JNK/SAPK), (3) the p38 group of protein kinases and (4) ERK5. The focus of this thesis is the p38 kinases, also called stress-activated protein kinases (SAPKs) together with the JNKs, because are activated by environmental and genotoxic stresses. This subfamily comprises four different p38 isoforms: p38α, p38β, p38γ and p38δ. Due to the availability of specific inhibitors and animal models for p38α and p38β, the role of these two kinases has been broadly studied. However, much less is known about the physiological implications of p38γ and p38δ. The main objective of this thesis is to broaden our knowledge about the functions of p38γ and p38δ, also called alternative p38s, in homeostasis and disease, taking advantage of full knockout or conditional knockout mice for these kinases. Besides, to better understand their biological implications at the molecular level we used in vitro models and basic biochemistry. Our data shows that the p38 MAPK isoforms are differentially regulated by their up-stream kinases, MKK3 and MKK6 in a tissuespecific manner. Besides, the p38γ and p38δ isoforms have very distinctive expression patterns in comparison with the ubiquitous expression of p38α and p38β, which suggests highly specialized cellular functions for these p38 isoforms. We demonstrate that p38γ and p38δ are essential in the regulation of inflammatory responses and key players in the development of liver inflammatory-mediated diseases such as acute hepatitis and steatosis. In these contexts, they play partially redundant roles, and the inhibition of both kinases is necessary to protect against the disease progression. Moreover, p38γ and p38δ are also involved in the control of cardiac growth and in the development of cardiomyopathies. We have shown that their expression and activation in the heart are developmentally upregulated during early postnatal stages of cardiac development. Besides, we report for the first time that p38γ and p38δ interact and cooperate in the regulation of both physiological and pathological cardiac hypertrophic growth. Our findings indicate that p38γ and p38δ are potential targets for the treatment of liver inflammatory-mediated diseases and cardiac hypertrophy.