Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies

Biological research: BR

article

Ramos-Kuri, Manuel¹  Meka, Sri Harika⁴  Salamanca-Buentello, Fabio⁵  Hajjar, Roger J.⁶  Lipskaia, Larissa⁷  Chemaly, Elie R.⁴ 

[1] Instituto Nacional de Cancerología, Secretarìa de Salud/Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México;Researcher of the Facultad de Bioética, Universidad Anáhuac;Centro de Investigación en Bioética y Genética;Division of Nephrology, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Clinical and Translational Research Center;University of Toronto Institute of Medical Science;Phospholamban Foundation;INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, and Université Paris-Est Créteil (UPEC)

关键词: Ras-opathies;    H-Ras gene;    K-Ras gene;    Ras pathway;    Physiological hypertrophy;    Pathological hypertrophy;    MAP kinase;    Calcineurin;   

DOI  :  10.1186/s40659-021-00342-6

来源: BioMed Central

【 摘 要 】

The Ras family of small Guanosine Triphosphate (GTP)-binding proteins (G proteins) represents one of the main components of intracellular signal transduction required for normal cardiac growth, but is also critically involved in the development of cardiac hypertrophy and heart failure. The present review provides an update on the role of the H-, K- and N-Ras genes and their related pathways in cardiac diseases. We focus on cardiac hypertrophy and heart failure, where Ras has been studied the most. We also review other cardiac diseases, like genetic disorders related to Ras. The scope of the review extends from fundamental concepts to therapeutic applications. Although the three Ras genes have a nearly identical primary structure, there are important functional differences between them: H-Ras mainly regulates cardiomyocyte size, whereas K-Ras regulates cardiomyocyte proliferation. N-Ras is the least studied in cardiac cells and is less associated to cardiac defects. Clinically, oncogenic H-Ras causes Costello syndrome and facio-cutaneous-skeletal syndromes with hypertrophic cardiomyopathy and arrhythmias. On the other hand, oncogenic K-Ras and alterations of other genes of the Ras-Mitogen-Activated Protein Kinase (MAPK) pathway, like Raf, cause Noonan syndrome and cardio-facio-cutaneous syndromes characterized by cardiac hypertrophy and septal defects. We further review the modulation by Ras of key signaling pathways in the cardiomyocyte, including: (i) the classical Ras-Raf-MAPK pathway, which leads to a more physiological form of cardiac hypertrophy; as well as other pathways associated with pathological cardiac hypertrophy, like (ii) The SAPK (stress activated protein kinase) pathways p38 and JNK; and (iii) The alternative pathway Raf-Calcineurin-Nuclear Factor of Activated T cells (NFAT). Genetic alterations of Ras isoforms or of genes in the Ras-MAPK pathway result in Ras-opathies, conditions frequently associated with cardiac hypertrophy or septal defects among other cardiac diseases. Several studies underline the potential role of H- and K-Ras as a hinge between physiological and pathological cardiac hypertrophy, and as potential therapeutic targets in cardiac hypertrophy and failure.

【 授权许可】

Unknown