Abstract
G-protein coupled receptor (GPCR) kinase 2 (GRK2) is upregulated in heart failure (HF) patients and mouse models of cardiac disease. GRK2 is a regulator of β-adrenergic receptors (βARs), a GPCR involved in ionotropic and chronotropic responses. We and others have recently reported GRK2 to be localized in the mitochondria, although its function in the mitochondria and/or metabolism remain not clearly defined. We hypothesized that upregulation of GRK2 reduced mitochondrial respiratory function and responses to βAR activation. Utilizing isolated mouse primary adult cardiomyocytes (ACMs), we investigated the role of glucose, palmitate, ketone bodies, and BCAAs in mediating cell survival. Our results showed that myocyte upregulation of GRK2 promotes palmitate-induced cell death. Isotopologue labeling and mass spectrometry showed that the upregulation of GRK2 reduces β-hydroxybutyryl CoA generation. Next, using isoproterenol (ISO), a non-selective βAR-agonist, we determined mitochondrial function in mouse and human primary ACMs. Upregulation of GRK2 impaired ISO-mediated mitochondrial functional responses, which we propose is important for metabolic adaptations in pathological conditions. Increased cardiac levels of GRK2 reduced fatty acid-specific catabolic pathways and impaired ISO-stimulated mitochondrial function. Our data support the notion that GRK2 participates in bioenergetic remodeling and may be an important avenue for the development of novel pharmacological strategies in HF.
Highlights
Heart failure (HF) is the leading cause of death in the US resulting in hospitalizations, pharmacological interventions, and lifestyle alterations [1]
We and others have reported that GPCR kinase 2 (GRK2) is localized to the mitochondria [5–7], where it plays a role in myocardial fatty acid utilization in cardiomyocytes [8,9]
As substrate preference and metabolic pathways are altered during development and cardiac pathologies [10], we sought to further understand how cardiac GRK2 in the adult heart may be altering metabolic networks that facilitate cardiac dysfunction
Summary
Heart failure (HF) is the leading cause of death in the US resulting in hospitalizations, pharmacological interventions, and lifestyle alterations [1]. The β-adrenergic receptor (βAR) is a major cardiac G-protein coupled receptor (GPCR) system involved in ionotropic and chronotropic responses [1]. Murine and human studies have shown that cardiac outcomes in HF are inversely proportional to myocardial levels of GPCR kinase 2 (GRK2) [3,4], a major regulator of cardiac βAR signaling [1]. We and others have shown that GRK2 is localized to mitochondria [5–7], where the function of this enzyme in this organelle is dependent on localization and kinase activity [8]. We and others have shown that GRK2 plays a role in metabolism, in cardiomyocyte fatty acid utilization [8,9], yet specific mechanisms of action and cardiac. IHoeernee, rwgeetpicrohvoimdeeeovsitdaesnisceof ACMs, wthhaitcuhpmreagyulcaotinontriobfucaterdtioacHGFRdKi2s,eeavseenpirnogthreesasbisoenn.ce of cardiac injury/stress, modifies bioenUertgileitzicinhgoma emosotuassies mofoAdCeMl os,fwcahridchiamc-asypceocnifitrcibGutrekt2ooHvFerdeisxeparseespsrioognre(Gssriokn.TG) [12], we Utilizing a mouse model of cardiac‐specific Grk overexpression (Grk2TG) [12], we iinnvveessttiiggaateteddwwhehtehtehreurpurepgruelgautiloantioofnGoRfKG2RinK2ACinMAs CalMtersedaltmeeretadbomlicetpaabtohlwicaypsatthhawt ays that mmaayy pprree‐-ddisipsposoesethtehehehaertarftorfodretdriemtreinmtaelnotaultcooumtecso. TThhese ddaattaassuupppporotrtthtehneontiootniothnaththaet tmheecmhaencihstaicniinsvtioclvinevmoelnvteomf GenRtKo2fiGn HRKF 2goinesHbeFygoondes beyond GGPCCRR‐-rreegguulaltaiotinonanadnmdamy apyropvirdoevaidneovaenl oavveenluaevfeonrupehaformr apchoalorgmicaacloinlotegrivceanltionnte. rvention
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