Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies

摘要

Ras and its related pathways. See text and references [1, 15, 21, 24, 44, 51, 52, 58, 60, 62] for details. (1) Ras: one of the central regulators of all the pathways shown. The activity of Ras is amplified by Guanine nucleotide exchange factors (GEFs) such as Sos and reduced by GTPase-activating proteins (GAP) such as Neurofibromin 1 (NF1). Ras is activated by various receptors at the cell membrane cell, particularly GPCR. (2) Upstream activators of Ras: GPCR Various stimuli activate GPCR, mainly Angiotensin II (AngII), through its type 1 receptor (Gq), and norepinephrine through its α1-adrenergic receptor (Gq) and β-adrenergic receptor (Gs). The subunit Gαs activates adenylate cyclase, which produces cyclic adenosine monophosphate (cAMP). Gq activates phospholipase C (PLC) which hydrolyzes phosphatidylinositol-4,5-bisphosphate (PIP2) to produce inositol-1,4,5-trisphosphate (IP3) and diacyl-glycerol (DAG). IP3 releases Ca++ from the sarco-endoplasmic reticulum through the IP3 receptor (IP3R). Ca++ and DAG activate protein kinase C (PKC). Ca++ activates calcineurine and calcineurine dephosphorylates and activates the cytosolic transcription factor NFAT-3 (Nuclear Factor of Activated T cells), inducing its nuclear translocation. Gq also activates Ras directly. Gs The action of the β-adrenergic receptor through Gs enhances cardiomyocyte contraction and relaxation. cAMP activates protein kinase A (PKA) which phosphorylates the L-type calcium channel (LTCC), facilitating voltage-gated Ca++ and entry and Ca++-induced Ca++ release from the sarco-endoplasmic reticulum through the Ryanondin receptor (RyR). RyR is also phosphorylated by PKA. PKA phosphorylates phospholamban (PLN) and lifts the inhibition on the sarco-endoplasmic reticulum Ca++ ATP-ase (SERCA), further enhancing cardiomyocyte function by facilitating Ca++ cycling. Ca++ can in turn bind to calcineurin. cAMP activates the GEF-Epac (exchange protein directly activated by cAMP). (3) Downstream effectors of Ras: MAP-Kinases Ras activates the Kinase pathways ERK, JNK and p38. The ERK pathway is related to physiological hypertrophy [25, 100, 109]. In contrast, the p38 and JNK, (known as SAPKs) pathways are activated by stress-related stimuli, and mediate pathological remodeling [62]. Ca++/Calcineurin This is the main pathway for pathological hypertrophy, also activated by Raf. Akt pathway Ras activates Akt through PI3K, with a dual cardio-protective effect, inhibition of apoptosis and pro-survival action, through NF-kB activation and NFAT inhibition [35]. However, NF-kB and GSK (Glycogen Synthase Kinase) can exert either pro- or anti-apoptotic effects. Cross-talk points are shown with a red arrow: (i) between Ras and the Calcineurin pathway through Raf [24, 25]. (ii) Between Adenylate cyclase and Ras pathways, with activation of Ras through Epac by cAMP. (iii) activation of ERK from PKA; and: (iv) Inhibition of NFAT by GSK