Silencing of peroxisome proliferator‐activated receptor‐alpha alleviates myocardial injury in diabetic cardiomyopathy by downregulating 3‐hydroxy‐3‐methylglutaryl‐coenzyme A synthase 2 expression

Abstract

Diabetic cardiomyopathy (DCM) is a cardiac disorder, which affects around 12% diabetic patients, resulting in overt heart death. Our initial bioinformatic analysis identified the differentially expressed gene 3‐hydroxy‐3‐methylglutaryl‐coenzyme A synthase 2 (HMGCS2) in DCM, which may be activated by peroxisome proliferator‐activated receptor‐alpha (PPARα) based on previous evidence. Therefore, the present study aims to explore the effect of PPARα on the development of DCM through regulating HMGCS2. The expression of PPARα and HMGCS2 was detected by reverse transcription quantitative polymerase chain reaction in cardiomyocytes and high‐glucose‐cultured cardiomyocytes. The proliferation and apoptosis of cardiomyocytes were examined by 5‐ethynyl‐2′‐deoxyuridine assay and flow cytometry, separately. Mitoehondrial membrane potential (MMP) and intracellular reactive oxygen species (ROS) levels were determined. Then, the protein levels of B‐cell lymphoma 2, Bcl‐2‐associated X protein, and cleaved Caspase‐3 were detected by Western blot analysis. The myocardial apoptosis index, heart weight, and serum lipids of rats were examined. At last, the expressions of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), transforming growth factor β1 (TGFβ1), peroxisome proliferator activator receptor gamma coactivator‐1 alpha (PGC1α), nuclear respiratory factor (NRF)‐1, NRF‐2, NAD(P)H oxidase 1, and superoxide dismutase‐1 were examined. HMGCS2 was the most differentially expressed gene in DCM. The levels of HMGCS2 and PPARα were upregulated in patients with DCM. HMGCS2 silencing was shown to inhibit HMGCS2 expression to suppress the apoptosis of high‐glucose‐induced cardiomyocytes and the loss of MMP, reduce the accumulation of ROS, and promote cardiomyocyte proliferation. Silencing of HMGCS2 and PPARα alleviated myocardial injury, decreased blood glucose, and lipid in DCM rats, downregulated the expression of ANP, BNP, and TGFβ1 to reduce myocardial injury, and elevated PGC1α, NRF‐1, and NRF‐2 levels to enhance oxidative stress levels. Our results demonstrated that silencing of PPARα could alleviate cardiomyocyte injury and oxidative stress via a mechanism related to the downregulation of HMGCS2, which could provide a novel target for DCM treatment.

LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease

“…HMGCS2 is a mitochondrial enzyme that catalyzes the first reaction of ketogenesis and related research has mainly focused on its roles in diabetes, tumor, Alzheimer's disease, and intestinal cell differentiation (Shi et al , 2017 ; Wang et al , 2017 , 2019b , 2020b ; Wan et al , 2018 ; Kim et al , 2019 ; Tomita et al , 2020 ). Increased HMGCS2 expression in diabetes enhanced the production of ketone bodies, thus leading to diabetic cardiomyopathy (Wang et al , 2020a ), whereas the function of HMGCS2 in diabetic nephropathy remains controversial. Tomita et al ( 2020 ) reported that SGLT2 inhibitors promoted ketone body rise through HMGCS2, thereby inhibiting mTORC1 in proximal renal tubules, explaining the protective effect of SGLT2 inhibitors on kidney.…”

“…HMGCS2 has been suggested to play important roles in diabetes, tumor, Alzheimer's disease, and intestinal cell differentiation (Wan et al , 2018 , 2019 ; Cheng et al , 2019 ; Kim et al , 2019 ; Zou et al , 2019 ; Wang et al , 2019b ). Recent data indicated that high HMGCS2 expression caused reactive oxygen species (ROS) accumulation and loss of the mitochondrial membrane potential (MMP), which then induced diabetic cardiomyopathy (Wang et al , 2020a ). However, the exact role of HMGCS2 in renal fibrosis remains unclear.…”

HMGCS2 silencing attenuates high glucose-induced in vitro diabetic cardiomyopathy by increasing cell viability, and inhibiting apoptosis, inflammation, and oxidative stress

“…Li et al showed that exercise training could reverse lipotoxicity-induced cardiomyopathy by repressing HMGCS2 [ 35 ]. Wang et al demonstrated that silencing of peroxisome proliferator-activated receptor-alpha alleviated myocardial injury in DCM by repressing HMGCS2 expression [ 39 ]. Sikder et al showed that circulating HMGCS2 was elevated in the high-fat diet-induced diabetic rats [ 40 ].…”

Transcriptomics Coupled to Proteomics Reveals Novel Targets for the Protective Role of Spermine in Diabetic Cardiomyopathy

“…DbCM is a common and severe complication of T1D with an increased incidence rate globally [ 1 , 2 , 29 ]. DbCM is manifested with diastolic function impairments and heart failure at the early stage, which contributes to the early morbidity and high mortality of T1D patients [ 30 , 31 ]. Multifactorial pathogenesis was observed in the progress of DbCM, such as metabolic disorders, autonomic dysfunction, abnormal homeostasis, interstitial fibrosis, and structural protein alteration [ 1 , 32 ].…”