Impact of Diabetes Mellitus on Left Ventricular Longitudinal Function of Patients with Non-Ischemic Dilated Cardiomyopathy

Tanaka, Hidekazu; Tatsumi, Kazuhiro; Matsuzoe, Hiroki; Matsumoto, Kensuke; Hirata, Ken–ichi

doi:10.21203/rs.3.rs-24152/v1

Cited by 6 publications

(7 citation statements)

References 26 publications

(32 reference statements)

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“…Diabetes mellitus is an independent risk of heart failure (HF), while HF could accelerate diabetes mellitus cardiovascular complication [5], according to a report, 15%-35% of HF patients should blamed to diabetic patients [34]. What's more, diabetic cardiomyopathy is considered an indispensable pathophysiological state among diabetic patients which could result in the dysfunctional cardiomyocytes, abnormal myocardial and the nal cardiac dysfunction characterized by left ventricular longitudinal dysfunction [8,35,36]. However, the therapy or speci c treatment of DCM in clinical is a considerable challenge.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Long non-coding RNA ZFAS1 attenuates pathogenic ferroptosis by sponging miR-150-5p to activate CCND2 against diabetic cardiomyopathy

Ni¹,

Chen²,

Huang³

et al. 2021

Preprint

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Background Diabetic cardiomyopathy (DCM) needs to be responsible for the increasing morbidity and mortality in diabetic patients with heart failure. Unfortunately, the pathogenesis of DCM has yet to be elaborate. Here we investigate the important role of lncRNA-ZFAS1 in the pathological process of DCM associated with ferroptosis. Methods Microarray data analysis of DCM in the patients or mice model from GEO was presented that ZFAS1 was significantly upregulated, miR-150-5p and CCND2 were significantly downregulated. High glucose (HG)-treated cardiomyocytes and db/db mice were simulated DCM in vitro and in vivo. Ad-ZFAS1, Ad-sh-ZFAS1, mimic miR-150-5p, Ad-CCND2, Ad-sh-CCND2 were injected into mice model or transfected into HG-treated Cardiomyocytes to clarify whether ZFAS1 can regulate miR-150-5p and CCND2 on ferroptosis. Effect of ZFAS1 on the left ventricular myocardial tissues in db/db mice and HG-treated cardiomyocytes, ferroptosis and apoptosis was determined by Masson staining, immunohistochemical staining, western blot, MBB staining, immunofluorescence staining and JC-1staining. The relationship among ZFAS1, miR-150-5p, CCND2 was identified by dual luciferase reporter assay and RNA Pull-down assay. Results Inhibition of ZFAS1 led to the reduced collagen deposition, decreased cardiomyocytes apoptosis, ferroptosis and attenuated the DCM progress. ZFAS1 can sponge miR-150-5p to regulate CCND2 expression. Ad-sh-ZFAS1, miR-150-5p mimic and Ad-CCND2 transfection contributed to attenuate ferroptosis and DCM both in vitro and in vivo, while transfection Ad-ZFAS1could reverse the positive effect of miR-150-5p mimic and Ad-CCND2 both in vitro and in vivo. Conclusion lncRNA-ZFAS1 acted as a ceRNA to sponge miR-150-5p can regulate CCND2 to promote cardiomyocytes ferroptosis and developed DCM, and inhibition of ZFAS1 could be a promising therapeutic target for the treatment and prevention of DCM.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the Long non-coding RNA ZFAS1 attenuates pathogenic ferroptosis by sponging miR-150-5p to activate CCND2 against diabetic cardiomyopathy

Ni¹,

Chen²,

Huang³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…In another word, T2DM exacerbates the prognosis of HF. Moreover, studies show that HF is an independent predictor of clinical prognosis, whether fatal or nonfatal, in diabetic patients [8][9][10][11]. The interaction between HF and T2DM makes the prognosis of patients more unsatisfactory.…”

Section: Introductionmentioning

confidence: 99%

Empagliflozin in the treatment of heart failure and type 2 diabetes mellitus: Evidence from several large clinical trials

Liang¹,

Gu²

2022

Int. J. Med. Sci.

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Heart failure coexists with type 2 diabetes mellitus, which seriously affects the clinical treatment and prognosis. At present, the treatment for patients with established heart failure and type 2 diabetes mellitus is usually combined with two treatment strategies for heart failure and type 2 diabetes mellitus. Recently, increasing studies showed that empagliflozin, a sodium-glucose co-transporter-2 inhibitor, has a positive effect on the treatment of patients with established heart failure and type 2 diabetes mellitus. Here, we summarize the latest and current understanding of the management for patients with established heart failure and type 2 diabetes mellitus and further present contemporary treatment options, sodium-glucose co-transporter-2 inhibitor, for these particular populations.

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“…DCM hearts are characterized by cardiac remodeling, early onset of diastolic dysfunction followed by systolic impairment, and eventually progresses to heart failure with reduced ejection fraction (HFrEF) [3]. Compared to coronary artery disease induced dilated cardiomyopathy, DCM has worse prognosis [4,5]. Compared to other cardiomyopathies, DCM exhibit metabolic dysfunction, electrophysiology, and insulin resistance [6,7] -making DCM management much more challenging.…”

Section: Introductionmentioning

confidence: 99%

Hypoglycemia Induced Mitochondrial Connexin-43 Accumulation Aggravates Diabetic Cardiomyopathy

Xing

Chang

et al. 2021

Preprint

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Background: Diabetic cardiomyopathy (DCM) is a complex multifaceted disease responsible for elevated hospitalization and mortality in patients with diabetes mellitus (DM). DCM patients exhibit subclinical diastolic dysfunction, progression towards systolic impairment, and abnormal electrophysiology. Hypoglycemia events that occur spontaneously or due to excess insulin administration threaten the lives of DM patients – with the increased risk of sudden death. However, the molecular underpinnings of hypoglycemia-aggravated DCM remain to be elucidated. Methods and Results: Here we used the established streptozotocin-induced type 1 diabetic cardiomyopathy (T1 DCM) murine model to investigate how hypoglycemia aggravates DCM progression. We showed that chronic hyper- or hypoglycemic challenges dampened cardiac diastolic function in vivo as well as myocardial contractility and calcium handling in isolated cardiomyocytes. Similar contractile defects were recapitulated using neonatal mouse ventricular myocytes (NMVMs) under glucose fluctuation challenges. Using immunoprecipitation mass spectrometry, we identified and validated that hypoglycemia challenge activates the MEK/ERK and PI3K/Akt pathways which results in Cx43 phosphorylation by Src protein in cardiomyocytes. Cx43 dissociation and accumulation at mitochondrial inner membrane was confirmed both in human and murine cardiomyocytes. To determine causality, we overexpressed a mitochondrial targeting Cx43 (mtCx43) using AAV2. At normal blood glucose levels, mtCx43 overexpression recapitulated cardiomyocytes contractile deficiencies, cardiac diastolic dysfunction as well as aberrant electrophysiology both in vitro as well as in vivo. Conclusions: Hypoglycemia challenges results in the accumulation of mtCx43 through the MEK/ERK/Src and PI3K/Akt/Src pathways. We provide evidence that Cx43 mislocalization is present in diabetes mellitus patient hearts, STZ-induced DCM murine model, and glucose fluctuation challenged NMVMs. Mechanistically, we demonstrated that mtCx43 is responsible for inducing aberrant contraction and disrupts electrophysiology in cardiomyocytes and our results support targeting of mtCx43 in treating DCM. Translational perspective: Severe hypoglycemia drives cardiac dysfunction and aggressive ventricular arrhythmias in patients with DCM that leads to sudden cardiac death. Here we demonstrate that Cx43 mislocalization to mitochondria occurs upon hypoglycemic challenge and mtCx43 accumulation is responsible for cardiac diastolic dysfunction, cardiomyocyte contractile dysfunction, and aberrant electrophysiology in vivo. Our findings give support for therapeutic targeting of MEK/ERK/Src and PI3K/Akt/Src pathways to prevent mtCx43-driven DCM.

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Impact of Diabetes Mellitus on Left Ventricular Longitudinal Function of Patients with Non-Ischemic Dilated Cardiomyopathy

Cited by 6 publications

References 26 publications

Inhibition of the Long non-coding RNA ZFAS1 attenuates pathogenic ferroptosis by sponging miR-150-5p to activate CCND2 against diabetic cardiomyopathy

Inhibition of the Long non-coding RNA ZFAS1 attenuates pathogenic ferroptosis by sponging miR-150-5p to activate CCND2 against diabetic cardiomyopathy

Empagliflozin in the treatment of heart failure and type 2 diabetes mellitus: Evidence from several large clinical trials

Hypoglycemia Induced Mitochondrial Connexin-43 Accumulation Aggravates Diabetic Cardiomyopathy

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