Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies

Abstract

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. Graphic abstract

Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts

“…Within the RAS system, the ACE2/Ang 1–7/Ang 1–9/MasR axis counterposes the ACE1/Ang II/AT1 receptor axis. With a homologous catalytic domain as for ACE1, ACE2 competes with ACE1 to convert Ang II to Ang 1–7 and Ang 1–9, which provides anti-vasoconstrictive, anti-inflammatory, anti-hypertrophic, and antifibrotic effects on various tissue including the cardiomyocytes by inhibiting NFAT [ 25 , 26 ]. Thus, inhibiting the RAS and activating the counterbalancing ACE2/Ang 1–7/Ang 1–9/MasR axis might have complementary action in cardiovascular diseases, including heart failure progression [ 27 ].…”

Novel p38 Mitogen-Activated Protein Kinase Inhibitor Reverses Hypoxia-Induced Pulmonary Arterial Hypertension in Rats

“…p38 MAPK signaling is directly involved in the progression of ventricular dysfunction, because it promotes cardiomyocyte adaptation to different stressors, which in turn triggers mechanisms of cardiac inflammation and further stimulates fibrosis [ 14 , 15 , 46 , 47 ]. Cardiac activation of caspase-3 leads to an ongoing apoptotic process in RV tissue in PH rats, indicating a transitioning to failing phenotype in RV myocytes [ 16 , 48 ].…”

Hsa_circ_0003748 promotes disease progression in rheumatic valvular heart disease by sponging miR‐577

“…Genetic changes in Ras isoforms or genes in the Ras‐MAPK pathway also lead to heart disease. 26 , 27 Lin et al 28 found that silencing miR‐665 restored cardiac function in rats with heart failure through the cAMP signaling pathway and overexpression of GLP1R. Qin et al 29 found that overexpressing miR‐22‐5p altered the miR‐22‐5p target gene Rap1a and the RAP1/ERK signaling pathway and affected the progression of myocardial injury.…”

“…The Ras family of small guanosine triphosphate‐binding proteins in the Ras signaling pathway is essential for intracellular signal transduction for cardiac growth and is involved in the development of cardiac hypertrophy and heart failure. Genetic changes in Ras isoforms or genes in the Ras‐MAPK pathway also lead to heart disease 26,27 . Lin et al 28 found that silencing miR‐665 restored cardiac function in rats with heart failure through the cAMP signaling pathway and overexpression of GLP1R.…”