Nuclear-mitochondrial communication involving miR-181c plays an important role in cardiac dysfunction during obesity

Román, Bárbara; Kaur, Pawandeep; Ashok, Deepthi; Kohr, Mark J.; Biswas, Roopa; O’Rourke, Brian; Steenbergen, Charles; Das, Samarjit

doi:10.1016/j.yjmcc.2020.05.009

Cited by 14 publications

(22 citation statements)

References 64 publications

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“…Overexpression of miR-181c in rats causes oxidative stress, which leads to cardiac dysfunction [1], similar to the reported upregulation of miR-181c in human cardiac dysfunction [4]. Recently, it has been identified that myocardial lipid accumulation due to high fat diet (HFD) consumption upregulates miR-181c expression in the heart [5]. Mitochondria activate reactive oxygen species (ROS) production in a type 2 diabetes (T2D) diet-induced obesity (DIO) model, indicating a significant role for mitochondrial dysfunction in glucose homeostasis and insulin resistance [6][7][8].…”

Section: Introductionsupporting

confidence: 69%

“…As shown previously, c/d KO mice were born in the expected Mendelian ratios and there were no body weight differences at birth compared to WT littermates [3]. Based on our observed finding that the hearts of c/d KO mice are protected against ischemia-reperfusion injury [3] and diet-induced obesity associated cardiac dysfunction [5], we hypothesized that c/d KO mice would also be protected from metabolic stress in the liver due to HF. Prior to HF exposure, c/d KO mice had increased oxygen consumption (VO 2 ; Figure 1A) compared to WT mice (p=0.01), but no differences in CO 2 production (Figure 1B).…”

Section: Metabolic Profile Of Mice Lacking Mir-181c/dmentioning

confidence: 54%

“…Recent data shows that the HF upregulates miR-181c in the heart [5]. To determine the regulation of miR-181c in the liver during diet-induced metabolic stress, we measured the expression of miR181c in WT-mice after exposure to 26 weeks of HF diet.…”

Section: Effect Of Hf Diet On Liver Mir-181c Expressionmentioning

confidence: 99%

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Role of miR-181c in Diet-Induced Obesity Through Regulation of Lipid Synthesis in Liver

Akiyoshi¹,

Boersma²,

Johnson³

et al. 2021

Preprint

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We recently identified a nuclear-encoded miRNA (miR-181c) in cardiomyocytes that can translocate into mitochondria to regulate mitochondrial gene (mt-COX1), and influence obesity-induced cardiac dysfunction through mitochondrial pathway. Liver plays a pivotal role during obesity. Therefore, we hypothesized that miR-181c plays an important role in pathophysiological complications associated with obesity. We used miR-181c/d-/- mice to study the miR-181c role in lipogenesis in hepatocytes during diet-induced obesity (DIO). Indirect calorimetric measurements were made during the 26 weeks high fat diet (HFD) exposure. qPCR was performed to examine the gene expression involved in lipid synthesis. Here, we show that miR-181c/d-/- mice are not protected against all metabolic consequences of HFD exposure. After 26 weeks of the HFD, miR-181c/d-/- mice had a significantly higher body fat (%) compared to WT. Glucose tolerance tests showed hyperinsulinemia and hyperglycemia, indicative of insulin insensitivity in the miR-181c/d-/- mice. HFD-fed miR-181c/d-/- mice had higher serum and liver triglyceride levels compared to HFD-fed WT mice. qPCR data demonstrated that several genes which are regulated by isocitrate dehydrogenase 1 (IDH1) were upregulated in miR-181c/d-/- liver compared to WT liver. Furthermore, an AAV-8 was used to deliver miR-181c, in vivo, to validate the potential role of miR-181c in the liver. miR-181c delivery attenuate the lipogenesis by downregulating the same lipid synthesis genes in the liver. In hepatocytes, miR-181c regulates lipid biosynthesis by targeting IDH1. Taken together, the data indicate that overexpression of miR-181c can be beneficial for various lipid metabolism disorders.

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Section: Introductionsupporting

confidence: 69%

Section: Metabolic Profile Of Mice Lacking Mir-181c/dmentioning

confidence: 54%

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Role of miR-181c in Diet-Induced Obesity Through Regulation of Lipid Synthesis in Liver

Akiyoshi¹,

Boersma²,

Johnson³

et al. 2021

Preprint

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“…Previous studies have reported that mitochondria are critical integrators of signal transduction during the development of cardiac hypertrophy (34,35). It has been demonstrated that VDAC, which is associated with the outer mitochondrial membrane, interacts with IP3R on the ER through the molecular chaperone GRP75 that is thought to participate in the refolding of proteins translocated into this organelle (36). VDAC1 may be associated with both mPTP opening and mitochondrial membrane depolarization.…”

Section: Discussionmentioning

confidence: 99%

Difluoromethylornithine attenuates isoproterenol‑induced cardiac hypertrophy by regulating apoptosis, autophagy and the mitochondria‑associated membranes pathway

et al. 2021

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Myocardial hypertrophy is an independent risk factor of cardiovascular diseases and is closely associated with the incidence of heart failure. In the present study, we hypothesized that difluoromethylornithine (DFMO) could attenuate cardiac hypertrophy through mitochondria-associated membranes (MAM) and autophagy. Cardiac hypertrophy was induced in male rats by intravenous administration of isoproterenol (ISO; 5 mg/kg/day) for 1, 3,7 and 14 days. For DFMO treatment group, rats were given ISO (5 mg/kg/day) for 14 days and 2% DFMO in their water for 4 weeks. The expression of atrial natriuretic peptide (ANP) mRNA,heart parameters, apoptosis rate, fibrotic area and protein expressions of cleaved caspase3/9, GRP75, Mfn2, CypD and VDAC1 were measured to confirm the development of cardiac hypertrophy, apoptosis and autophagy induced by ISO. ANP mRNA and MAM protein expression levels were assessed by reverse transcription-quantitative PCR and western blotting to evaluate hypertrophy and the effects of DFMO oral administration. The results demonstrated that heart parameters, ANP mRNA levels, fibrotic area and apoptosis rate were significantly increased in the heart tissue for ISO 7 and 14 day groups compared with the control group. Furthermore, treatment with DFMO significantly inhibited these indicators, and DFMO downregulated the MAM signaling pathway and upregulated the autophagy pathway in heart tissue compared with the ISO 14 day group. Overall, all ISO-induced changes analyzed in the present study were attenuated following treatment with DFMO. The findings form this study suggested that DFMO treatment may be considered as a potential strategy for preventing ISO-induced cardiac hypertrophy.

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“…In addition, sirtuins, such as Sirt4 promotes hypertrophic growth, the generation of fibrosis and cardiac dysfunction by increasing ROS levels upon pathological stimulation [ 33 ]. Importantly, recent studies demonstrated that MICU1 downregulation in hearts was partly the results of decreased expression of transcriptions factor Sp1 [ 34 ]. These findings provide clue for understanding the regulatory mechanisms of MICU1 expression in hypertrophic hearts in our future research.…”

Section: Discussionmentioning

confidence: 99%

Melatonin alleviates angiotensin-II-induced cardiac hypertrophy via activating MICU1 pathway

Yang¹,

Du²,

Xu³

et al. 2020

Aging

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Mitochondrial calcium uptake 1 (MICU1) is a pivotal molecule in maintaining mitochondrial homeostasis under stress conditions. However, it is unclear whether MICU1 attenuates mitochondrial stress in angiotensin II (Ang-II)-induced cardiac hypertrophy or if it has a role in the function of melatonin. Here, small-interfering RNAs against MICU1 or adenovirus-based plasmids encoding MICU1 were delivered into left ventricles of mice or incubated with neonatal murine ventricular myocytes (NMVMs) for 48 h. MICU1 expression was depressed in hypertrophic myocardia and MICU1 knockdown aggravated Ang-II-induced cardiac hypertrophy in vivo and in vitro . In contrast, MICU1 upregulation decreased cardiomyocyte susceptibility to hypertrophic stress. Ang-II administration, particularly in NMVMs with MICU1 knockdown, led to significantly increased reactive oxygen species (ROS) overload, altered mitochondrial morphology, and suppressed mitochondrial function, all of which were reversed by MICU1 supplementation. Moreover, peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α)/MICU1 expression in hypertrophic myocardia increased with melatonin. Melatonin ameliorated excessive ROS generation, promoted mitochondrial function, and attenuated cardiac hypertrophy in control but not MICU1 knockdown NMVMs or mice. Collectively, our results demonstrate that MICU1 attenuates Ang-II-induced cardiac hypertrophy by inhibiting mitochondria-derived oxidative stress. MICU1 activation may be the mechanism underlying melatonin-induced protection against myocardial hypertrophy.

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Nuclear-mitochondrial communication involving miR-181c plays an important role in cardiac dysfunction during obesity

Cited by 14 publications

References 64 publications

Role of miR-181c in Diet-Induced Obesity Through Regulation of Lipid Synthesis in Liver

Role of miR-181c in Diet-Induced Obesity Through Regulation of Lipid Synthesis in Liver

Difluoromethylornithine attenuates isoproterenol‑induced cardiac hypertrophy by regulating apoptosis, autophagy and the mitochondria‑associated membranes pathway

Melatonin alleviates angiotensin-II-induced cardiac hypertrophy via activating MICU1 pathway

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