Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission

Wang, Qilong; Zhang, Miao; Torres, Gloria; Wu, Shengnan; Chen, Ouyang; Xie, Zhonglin; Zou, Ming‐Hui

doi:10.2337/db16-0915

Cited by 280 publications

(239 citation statements)

References 52 publications

(62 reference statements)

Supporting

Mentioning

224

Contrasting

Unclassified

Order By: Relevance

“…Recent studies have demonstrated that AMPK promotes both fusion and fission under different conditions, via direct and indirect mechanisms (Kang et al, 2016; Toyama et al, 2016; Wang et al, 2017). Our data show that chronic activation of AMPK maintains mitochondrial network homeostasis, however under normal physiological conditions the capacity to activate AMPK diminishes with age (Reznick et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling

et al. 2017

View full text Add to dashboard Cite

Summary Mitochondrial network remodeling between fused and fragmented states facilitates mitophagy, interaction with other organelles and metabolic flexibility. Aging is associated with a loss of mitochondrial network homeostasis, but cellular processes causally linking these changes to organismal senescence remain unclear. Here, we show that AMP-activated protein kinase (AMPK) and dietary restriction (DR) promote longevity in C. elegans via maintaining mitochondrial network homeostasis and functional coordination with peroxisomes to increase fatty acid oxidation (FAO). Inhibiting fusion or fission specifically blocks AMPK- and DR-mediated longevity. Strikingly however, preserving mitochondrial network homeostasis during aging by co-inhibition of fusion and fission is sufficient itself to increase lifespan, while dynamic network remodeling is required for intermittent fasting-mediated longevity. Finally, we show that increasing lifespan via maintaining mitochondrial network homeostasis requires FAO and peroxisomal function. Together these data demonstrate that mechanisms that promote mitochondrial homeostasis and plasticity can be targeted to promote healthy aging.

show abstract

Section: Discussionmentioning

confidence: 99%

Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling

et al. 2017

View full text Add to dashboard Cite

show abstract

“…DRP1inhibition suppresses vascular disease pathology in diabetic ApoE -deficient mice 13 , and balloon 12 and wire injury 65 rodent models. In contrast, heterozygous Drp1 -deficient mice did not have altered vascular pathology in a PCSK9-gain-of-function model, and DRP1 was not elevated in calcified plaque of the two most commonly used atherosclerosis mouse models, ApoE -deficient and Ldlr -deficient mice.…”

Section: Discussionmentioning

confidence: 99%

“…No mechanism has been suggested for the presence of cardiac calcification in these mice, and whether DRP1 regulates calcification of other tissues, including the vasculature is unknown. DRP1inhibition prevents rat vascular neointima formation in a balloon injury model 12 , suppresses lesion formation in diabetic ApoE -deficient mice 13 , and oxidized low density lipoprotein induces DRP1 mediated mitochondrial fragmentation in human SMCs 14 , suggesting a possible role of DRP1 in vascular disease. Reduced mitochondrial fusion protein, Mitofusin 2 (MFN2) that acts in an opposite function to that of DRP1 driven mitochondrial fission, is associated with atherosclerosis pathology in mice 15, 16 , rabbits 17 , and humans 16 .…”

Section: Introductionmentioning

confidence: 99%

Dynamin-Related Protein 1 Inhibition Attenuates Cardiovascular Calcification in the Presence of Oxidative Stress

et al. 2017

View full text Add to dashboard Cite

Rationale Mitochondrial changes occur during cell differentiation and cardiovascular disease. Dynamin-related protein 1 (DRP1) is a key regulator of mitochondrial fission. We hypothesized that DRP1 plays a role in cardiovascular calcification, a process involving cell differentiation and a major clinical problem with high unmet needs. Objective To examine the effects of osteogenic promoting conditions on DRP1, and whether DRP1 inhibition alters the development of cardiovascular calcification. Methods and Results DRP1 was enriched in calcified regions of human carotid arteries, examined by immunohistochemistry. Osteogenic differentiation of primary human vascular smooth muscle cells (SMCs) increased DRP1 expression. DRP1 inhibition in human SMCs undergoing osteogenic differentiation attenuated matrix mineralization, cytoskeletal rearrangement, mitochondrial dysfunction, and reduced type 1 collagen secretion and alkaline phosphatase activity. DRP1 protein was observed in calcified human aortic valves, and DRP1 RNA interference reduced primary human valve interstitial cell calcification. Mice heterozygous for Drp1 deletion did not exhibit altered vascular pathology in a PCSK9 gain-of-function atherosclerosis model. However, when mineralization was induced via oxidative stress, DRP1 inhibition attenuated mouse and human SMC calcification. Femur bone density was unchanged in mice heterozygous for Drp1 deletion, and DRP1 inhibition attenuated oxidative stress-mediated dysfunction in human bone osteoblasts. Conclusions We demonstrate a new function of DRP1 in regulating collagen secretion and cardiovascular calcification, a novel area of exploration for the potential development of new therapies to modify cellular fibrocalcific response in cardiovascular diseases. Our data also support a role of mitochondrial dynamics in regulating oxidative stress-mediated arterial calcium accrual and bone loss.

show abstract

“…Previous study indicated that metformin (300 mg/kg/d) attenuated the development of atherosclerosis by reducing mitochondrial fission in an AMPK-dependent manner, but there was no difference in metabolic parameters, including serum lipid and glucose metabolism, between diabetic mice treated with and without metformin [51]. It is speculated that LPS elicited a strong release of inflammatory cytokines which had been shown to impair insulin-mediated glucose disposal [52].…”

Section: Discussionmentioning

confidence: 99%

Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice

Yang

Dong

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Sepsis is a common disease that continues to increase in prevalence worldwide, and diabetes mellitus may make the situation worse. This study was designed to determine the role of Liver Kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in diabetic mice complicated with systemic endotoxemia. Methods: The effects of LKB1/AMPK signaling pathway activation on endotoxemia were investigated in streptozotocin induced diabetic mice (STZ-mice) and db/db diabetic mice. Primary peritoneal macrophages and human umbilical vein endothelial cells (HUVECs) monolayers were simultaneously stimulated by both high glucose and LPS and used as a model to investigate the potential molecular mechanisms in vitro. Results: After treatment with LPS, high glucose or both LPS and high glucose, phosphor-AMPK expression was decreased, and moreover, AMPK activation by metformin treatment alleviated the decrease in phosphor-AMPK expression in HUVECs and macrophages as well as in lung tissue. Furthermore, both LPS and high glucose co-treatment decreased LKB1 and phosphor-AMPK expression via enhanced oxidative stress response, and importantly, LKB1 overexpression mediated by adenovirus inhibited the decrease in phosphor-AMPK expression in macrophages and HUVECs. AMPK activation by metformin administration improved the survival of STZ-induced diabetic mice and db/db diabetic mice, which was associated with reduced lung endothelial hyperpermeability and systemic inflammatory response. Furthermore, the permeability of HUVECs monolayers induced by both high glucose and LPS stimulation was also alleviated by AMPK activation, which was partly via suppression of VE-cadherin phosphorylation. Conclusion: These data demonstrated that LKB1/AMPK signaling pathway activation improved the survival of diabetic mice complicated with endotoxemia. Thus, LKB1/AMPK signaling pathway may serve as a potentially useful therapeutic target for severe infection in diabetic patients.

show abstract

Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission

Cited by 280 publications

References 52 publications

Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling

Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling

Dynamin-Related Protein 1 Inhibition Attenuates Cardiovascular Calcification in the Presence of Oxidative Stress

Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice

Contact Info

Product

Resources

About