Cardiac‐specific deletion of FDPS induces cardiac remodeling and dysfunction by enhancing the activity of small GTP‐binding proteins

Abstract

The mevalonate pathway is essential for cholesterol biosynthesis. Previous studies have suggested that the key enzyme in this pathway, farnesyl diphosphate synthase (FDPS), regulates the cardiovascular system. We used human samples and mice that were deficient in cardiac FDPS (c-Fdps À/À mice) to investigate the role of FDPS in cardiac homeostasis. Cardiac function was assessed using echocardiography. Left ventricles were examined and tested for histological and molecular markers of cardiac remodeling. Our results showed that FDPS levels were downregulated in samples from patients with cardiomyopathy. Furthermore, c-Fdps À/À mice exhibited cardiac remodeling and dysfunction. This dysfunction was associated with abnormal activation of Ras and Rheb, which may be due to the accumulation of geranyl pyrophosphate. Activation of Ras and Rheb stimulated downstream mTOR and ERK pathways. Moreover, administration of farnesyltransferase inhibitors attenuated cardiac remodeling and dysfunction in c-Fdps À/À mice. These results indicate that FDPS plays an important role in cardiac homeostasis. Deletion of FDPS stimulates the downstream mTOR and ERK signaling pathways, resulting in cardiac remodeling and dysfunction.

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

“…Interestingly, the same group previously found that partial loss of FPPS activity with siRNA‐mediated knockdown or pharmacological inhibition ameliorated cardiac hypertrophy and fibrosis in response to pressure overload [10] or angiotensin II [11], respectively. These data, taken together with the cardiovascular protection afforded by statin drugs, indicate that dampening flux through the mevalonate pathway reduces adverse cardiac remodeling, whereas complete abolishment of this pathway using a clean genetic strategy is deleterious, resulting in cardiac decompensation and lethality [5]. Interestingly, enhanced generation of isoprenoids in cardiomyocytes can also be maladaptive, as transgenic mice with cardiomyocyte‐specific overexpression of FPPS similarly develop dilated cardiomyopathy and exhibit exacerbated cardiac damage in response to ischemia–reperfusion injury [12,13].…”

“…Wang, Zhang, Chen et al found accumulation of GPP and enhanced abundance of membrane‐associated Rheb and Ras in FPPS cKO hearts [5]. How could Rheb and Ras accumulate in the membrane without farnesylation?…”

“…Concomitant with increased membrane association, the authors observed profound enhancement of GTP‐loading on Rheb and Ras and downstream phosphorylation of mammalian target of rapamycin (mTOR) and extracellular signal‐regulated kinases 1 and 2 (ERK1/2) in FPPS cKO hearts (Figure 1). Wang, Zhang, Chen et al propose that, under the conditions of elevated GPP levels in hearts lacking FPPS, farnesyltransferase transfers the geranyl moiety to Rheb and Ras, resulting in hyperactivation of mTOR and ERK1/2 signaling that promotes cardiac hypertrophy and maladaptation [5]. This has some plausibility, given that recombinant farnesyltransferase is capable of transferring the 10‐carbon GPP as an alternate substrate in a purified in vitro system [14].…”

“…HMG-CoA, hydroxymethylglutaryl-CoA; IPP, isopentenyl pyrophosphate; DMAPP, dimethylallyl pyrophosphate; GPP, geranyl pyrophosphate; FPP, farnesyl pyrophosphate; GGPP, geranylgeranyl pyrophosphate; FPPS, farnesyl diphosphate synthase; GGPPS, geranylgeranyl pyrophosphate synthase; FTase, farnesyltransferase; GGTase, geranylgeranyl transferase; ERK, extracellular signal-regulated kinase; mTOR, mammalian target of rapamycin. cardiac remodeling, whereas complete abolishment of this pathway using a clean genetic strategy is deleterious, resulting in cardiac decompensation and lethality [5]. Interestingly, enhanced generation of isoprenoids in cardiomyocytes can also be maladaptive, as transgenic mice with cardiomyocyte-specific overexpression of FPPS similarly develop dilated cardiomyopathy and exhibit exacerbated cardiac damage in response to ischemiareperfusion injury [12,13].…”

“…In the future, metabolic labeling studies such as with bioorthogonal lipid probes amenable to click chemistry could clarify the promiscuity of protein prenylation machinery, including the role of farnesyltransferase and other enzymes in transferring the Mevalonate pathway in cardiac homeostasis 251 10-carbon geranyl group; the kinetics of this modification on Rheb, Ras, and other small GTPases; and if this occurs at the canonical cysteine on the C-terminal CAAX motif. Notably, FPPS mRNA and protein levels were substantially reduced in the hearts of patients with heart failure with reduced ejection fraction (HFrEF) [5], implicating FPPS in the molecular etiology of human heart failure. Collectively, studies by Wang, Zhang, Chen et al [5] and others [8,[10][11][12][13] have established that proper mevalonate pathway activity and protein prenylation are imperative for cardiac homeostasis but also dysregulated in heart failure.…”