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Increased CPT1a expression is a critical cardioprotective response to pathological stress that suppresses gene programs for remodeling and enables rescue by gene transfer

ABSTRACT: Carnitine palmitoyl transferase 1 (CPT1) is a rate-limiting enzyme for long chain fatty acid oxidation (FAO) in cardiac mitochondria. In adult hearts, CPT1b predominates, while CPT1a is co-expressed at lower levels. Pathological stress on the heart is known to induce CPT1a expression, but it’s role in pathological remodeling is unknown. CPT1 isoform expression was assayed in myocardium of human heart failure (HF) patients with nonischemic cardiomyopathy (NICM). To explore the role of CPT1a upregulation in response to pathological stress, mice were subjected to cardiac pressure overload via transverse aortic constriction (TAC) or sham surgery (sham) with cardiac-specific CPT1a knockdown or cardiac-specific, AAV9 mediated overexpression of CPT1a (AAV9.cTNTN.Cpt1a). MiR370, known to suppress hepatic CPT1a, was also overexpressed to determine if miR370 regulates cardiac CPT1a expression. CPT1a protein was elevated and miR370 reduced in myocardium of male and female NICM patients (204% vs. non-failing unused donor hearts), as well as in failing mouse hearts. AAV mediated miR370 overexpression in mouse hearts suppressed CPT1a expression and attenuated the response of CPT1a to TAC. Preventing CPT1a upregulation in response to TAC in cardiac specific CPT1a knockout mice (csCPT1a ko) exacerbated adverse remodeling during TAC, causing severe dysfunction and increased mortality. In contrast, CPT1a overexpression (2.8 fold), attenuated impaired ejection fraction (EF, by 54%), fractional shortening (FS, 65%) and +/-dp/dt, and reduced ANP expression and heart mass/tibia length vs. PBS-infused TAC hearts (p<0.05). Delivery of AAV9.cTnT.Cpt1a 4 wks after TAC surgery during cardiac dysfunction, led to significant rescue of EF and FS vs. animals receiving empty virus and mitigated the exacerbated dysfunction of csCPT1a ko hearts at 4 wks TAC. RNA-seq and reverse transcription-quantitative PCR revealed a novel function of CPT1a in suppressing hypertrophic, profibrotic and cell death gene programs in both sham and TAC hearts, irrespective of changes in FAO. The effects of CPT1a in the heart extend beyond FAO and include a non-canonical regulation of cardiac gene programs. In addition to an animal model of HF, CPT1a upregulation occurs in failing human hearts, and is a critical and cardioprotective adaptation to pathological stress that attenuates adverse cardiac remodeling.

ORGANISM(S): Mus musculus

PROVIDER: GSE268251 | GEO | 2026/01/21

REPOSITORIES: GEO

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Project description:<p>Increased protein acetylation is frequently observed in the failing heart, including in hearts with heart failure with preserved ejection fraction (HFpEF). However, the role of protein acetylation in cardiac metabolic impairments during the pathogenesis of HFpEF remains insufficiently investigated. In this study, a two-hit strategy, involving a high-fat diet and Nω-nitro-L-arginine methyl ester (L-NAME), was employed to induce the HFpEF model in mice. Significant cardiac diastolic dysfunction, pathological remodeling, and enhanced protein hyperacetylation were observed in the hearts of the two-hit HFpEF mice. Acetylome profiling revealed that the hyperacetylated proteins were predominantly localized to mitochondria and enriched in metabolic pathways, particularly in fatty acid oxidation (FAO). Furthermore, the HFpEF heart exhibited reduced FAO capacity and abnormal lipid accumulation. Activation of mitochondrial protein deacetylation restored FAO capacity and alleviated cardiac dysfunction in the HFpEF heart, whereas inhibition of mitochondrial deacetylase directly induced lipid metabolism disorders in cardiomyocytes. Notably, we identified Dlat, a pyruvate metabolism enzyme, as the key transacetylase responsible for mitochondrial protein hyperacetylation in the HFpEF heart. Overexpression of Dlat enhanced FAO-related protein acetylation and exacerbated cardiac lipid metabolism disturbances, thereby inducing pathological changes resembling the HFpEF phenotype. In contrast, Dlat knockdown effectively mitigated FAO inhibition and functional impairment in the two-hit HFpEF mice. Through discovery-driven approaches, we demonstrated that Dlat directly binds to the alpha subunit of mitochondrial trifunctional protein (HADHA) and triggers its acetylation at the K728 site, thereby inactivating HADHA enzymatic activity. Reactivating HADHA, either by cardiac-specific HADHA overexpression or oral administration of a biogenic polyamine, restored cardiac FAO capacity and prevented the development of HFpEF. Our study provides a mechanistic basis linking protein hyperacetylation, FAO inhibition, and the development of HFpEF. Activation of mitochondrial deacetylase or enhancement of cardiac FAO capacity may offer novel strategies for restoring cardiac metabolic homeostasis and function in HFpEF.</p>

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Project description:Increased protein acetylation is frequently observed in the failing heart, including in hearts with heart failure with preserved ejection fraction (HFpEF). However, the role of protein acetylation in cardiac metabolic impairments during the pathogenesis of HFpEF remains insufficiently investigated. In this study, a two-hit strategy, involving a high-fat diet and Nω-nitro-L-arginine methyl ester (L-NAME), was employed to induce the HFpEF model in mice. Significant cardiac diastolic dysfunction, pathological remodeling, and enhanced protein hyperacetylation were observed in the hearts of the two-hit HFpEF mice. Acetylome profiling revealed that the hyperacetylated proteins were predominantly localized to mitochondria and enriched in metabolic pathways, particularly in fatty acid oxidation (FAO). Furthermore, the HFpEF heart exhibited reduced FAO capacity and abnormal lipid accumulation. Activation of mitochondrial protein deacetylation restored FAO capacity and alleviated cardiac dysfunction in the HFpEF heart, whereas inhibition of mitochondrial deacetylase directly induced lipid metabolism disorders in cardiomyocytes. Notably, we identified Dlat, a pyruvate metabolism enzyme, as the key transacetylase responsible for mitochondrial protein hyperacetylation in the HFpEF heart. Overexpression of Dlat enhanced FAO-related protein acetylation and exacerbated cardiac lipid metabolism disturbances, thereby inducing pathological changes resembling the HFpEF phenotype. In contrast, Dlat knockdown effectively mitigated FAO inhibition and functional impairment in the two-hit HFpEF mice. Through discovery-driven approaches, we demonstrated that Dlat directly binds to the alpha subunit of mitochondrial trifunctional protein (HADHA) and triggers its acetylation at the K728 site, thereby inactivating HADHA enzymatic activity. Reactivating HADHA, either by cardiac-specific HADHA overexpression or oral administration of a biogenic polyamine, restored cardiac FAO capacity and prevented the development of HFpEF. Our study provides a mechanistic basis linking protein hyperacetylation, FAO inhibition, and the development of HFpEF. Activation of mitochondrial deacetylase or enhancement of cardiac FAO capacity may offer novel strategies for restoring cardiac metabolic homeostasis and function in HFpEF.

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Increased CPT1a expression is a critical cardioprotective response to pathological stress that suppresses gene programs for remodeling and enables rescue by gene transfer

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