Cardiac decompensation and promiscuous prenylation of small GTPases in cardiomyocytes in response to local mevalonate pathway disruption^†

Abstract

Investigations of major mevalonate pathway enzymes have demonstrated the importance of local isoprenoid synthesis in cardiac homeostasis. Farnesyl diphosphate synthase (FPPS) synthesizes isoprenoid precursors needed for cholesterol biosynthesis and protein prenylation. Wang, Zhang, Chen et al, in a recently published article in The Journal of Pathology, elegantly elucidated the pathological outcomes of FPPS deficiency in cardiomyocytes, which paradoxically resulted in increased prenylation of the small GTPases Ras and Rheb. Cardiomyocyte FPPS depletion caused severe dilated cardiomyopathy that was associated with enhanced GTP-loading and abundance of Ras and Rheb in lipidated protein-enriched cardiac fractions and robust activation of downstream hypertrophic ERK1/2 and mTOR signaling pathways. Cardiomyopathy and activation of ERK1/2 and mTOR caused by loss of FPPS were ameliorated by inhibition of farnesyltransferase, suggesting that impairment of FPPS activity results in promiscuous activation of Ras and Rheb through non-canonical actions of farnesyltransferase. Here, we discuss the findings and adaptive signaling mechanisms in response to disruption of local cardiomyocyte mevalonate pathway activity, highlighting how alteration in a key branch point in the mevalonate pathway affects cardiac biology and function and perturbs protein prenylation, which might unveil novel strategies and intricacies of targeting the mevalonate pathway to treat cardiovascular diseases.

Regulation of cardiomyocyte intracellular trafficking and signal transduction by protein palmitoylation

“…For instance, many G protein-coupled receptors (GPCRs) are palmitoylated on their C-terminal cytosolic tail, a majority of heterotrimeric Gα subunits are palmitoylated on their N-terminus, and some small GTPases have cysteines adjacent to the hypervariable region that undergo palmitoylation cycling (e.g. H-Ras, N-Ras) to dynamically control signaling output [ 1 , 41 , 48–50 ]. Palmitoylation is an optimal mechanism to rapidly activate or impart spatiotemporal control to intracellular signal transduction in cardiomyocytes and profoundly influence cardiac function and pathophysiology.…”

NADPH Oxidases in Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction

“…Similarly, the cardiomyocyte-specific loss of Rac1, which is required for the induction of NOX2 oxidase activity, rescues diastolic dysfunction in response to pressure overload [ 94 ] and suppresses cardiac hypertrophy, fibrosis, and oxidative stress in response to AngII [ 61 ] and streptozotocin-induced diabetes [ 83 ]. Moreover, statin treatment, which represses small GTPase signaling by inhibiting the biosynthesis of lipid precursors needed for protein prenylation [ 95 ], impairs myocardial Rac1 activation and oxidative stress in rats in response to AngII or pressure overload [ 96 ] and in human heart failure [ 97 ]. Statin treatment is also associated with reduced cardiomyocyte hypertrophy and resting tension in myocardium from patients with HFpEF [ 22 ], suggesting that an effective in vivo strategy to target NOX2 could alleviate cardiac maladaptation in HFpEF.…”

zDHHC9 Regulates Cardiomyocyte Rab3a Activity and Atrial Natriuretic Peptide Secretion Through Palmitoylation of Rab3gap1

“… 29 , 38 Rab3 proteins (Rab3a/b/c/d) associate with vesicle membranes via geranylgeranyl lipid modifications on their C-terminus, and, once activated, Rab3-GTP interacts with effectors to aide in docking and priming of DCVs for fusion with the plasma membrane. 37 , 39 , 40 , 41 Rab3 GTPase activating protein 1 (Rab3gap1) hydrolyzes GTP on Rab3a to enable its detachment from DCVs, thereby promoting successive rounds of exocytosis and secretion of DCV contents into the extracellular space. 38 , 39 , 40 Indeed, GTP hydrolysis and nucleotide cycling on Rab3a are required for complete docking, fusion pore opening, and exocytosis.…”