AMPK, Mitochondrial Function, and Cardiovascular Disease

In the paper

“In addition to its conventional roles as an intracellular energy switch or fuel gauge, emerging research has shown that AMPK is also a redox sensor and modulator, playing pivotal roles in maintaining cardiovascular processes and inhibiting disease progression.”

In the paper

“In humans, each subunit has multiple distinct isoforms encoded by different genes: the α-subunit has two isoforms, α1 and α2, encoded by gene PRKAA1 and PRKAA2, respectively [20]; the β-subunit has two isoforms, β1 and β2, encoded by gene PRKAB1 and PRKAB2, respectively [21]; and the γ-subunit has three isoforms, γ1, γ2, and γ3, encoded by gene PRKAG1, PRKAG2, and PRKAG3, respectively [22].”

What the sources say

• Not checked yetcites [20] Stapleton, 1996, Mammalian AMP-activated protein kinase subfamily, J. Biol. Chem. source
• Not checked yetcites [21] Thornton, 1998, Identification of a novel AMP-activated protein kinase beta subunit isoform that is highly expressed in skeletal muscle, J. Biol. Chem. source
• Not checked yetcites [22] Cheung, 2000, Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding, Biochem. J. source

In the paper

“Activation loop phosphorylation increases AMPK activity by about 100-fold, while allosteric regulation changes AMPK activity up to tenfold in mammalian cells and about twofold in recombinant, bacterially produced AMPK [26,28,38,39].”

What the sources say

• Not checked yetcites [26] Xiao, 2007, Structural basis for AMP binding to mammalian AMP-activated protein kinase, Nature source
• Not checked yetcites [28] Gowans, 2013, AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation, Cell Metab. source
• Not checked yetcites [38] Sanders, 2007, Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family, J. Biol. Chem. source
• Not checked yetcites [39] Davies, 1995, 5’-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC, FEBS Lett. source

In the paper

“ROS are plenty of free radicals and chemically reactive molecules derived from oxygen molecule [41].”

What the sources say

• Not checked yetcites [41] Alfadda, 2012, Reactive oxygen species in health and disease, J. Biomed. Biotechnol. source

In the paper

“Accumulating studies have demonstrated crosstalk between AMPK and mitochondria, such as AMPK regulation of mitochondrial homeostasis and mitochondrial dysfunction causing abnormal AMPK activity.”

In the paper

“Each AMPK complex is comprised of an α-subunit, a β-subunit, and a γ-subunit, and all possible combinations produce 12 different AMPK complexes [23].”

What the sources say

• Not checked yetcites [23] Ross, 2016, AMP-activated protein kinase: A cellular energy sensor that comes in 12 flavours, FEBS J. source

In the paper

“The γ-subunit allows AMPK to react to changes in the level of AMP, ADP, and ATP, as it includes four tandem cystathionine β synthase motifs that allow AMPK to bind adenine nucleotides [26].”

What the sources say

• Not checked yetcites [26] Xiao, 2007, Structural basis for AMP binding to mammalian AMP-activated protein kinase, Nature source

In the paper

“Excessive production of ROS, usually termed oxidative stress, are caused by increased production and/or insufficient presence of endogenous antioxidants [41].”

What the sources say

• Not checked yetcites [41] Alfadda, 2012, Reactive oxygen species in health and disease, J. Biomed. Biotechnol. source

In the paper

“Most ROS are generated as byproducts of mitochondrial electron transportation from the reduction of molecular oxygen to produce superoxide [41].”

What the sources say

• Not checked yetcites [41] Alfadda, 2012, Reactive oxygen species in health and disease, J. Biomed. Biotechnol. source

In the paper

“Oxidative stress is considered detrimental because of its damage to fats, deoxyribonucleic acid, and proteins in a cell, which can lead to numerous diseases such as diabetes, cancer, neurodegenerative disease, and cardiovascular disease (CVD) [41].”

What the sources say

• Not checked yetcites [41] Alfadda, 2012, Reactive oxygen species in health and disease, J. Biomed. Biotechnol. source

In the paper

“AMPK, a heterotrimeric complex, is composed of a catalytic α-subunit and beta (β) and gamma (γ) regulatory subunits [19].”

What the sources say

• Not checked yetcites [19] Yan, Y., Zhou, X.E., Xu, H.E., and Melcher, K. (2018). Structure and physiological regulation of AMPK. Int. J. Mol. Sci., 19. source

In the paper

“The β-subunit includes a carbohydrate-binding module that grants AMPK to bind to glycogen [25].”

What the sources say

• Not checked yetcites [25] Hudson, 2003, A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias, Curr. Biol. source

In the paper

“Lastly, allosteric AMPK activation can also occur in non-phosphorylated AMPK, with even higher fold activation than phosphorylated AMPK [40].”

What the sources say

• Not checked yetcites [40] Willows, 2017, Phosphorylation of AMPK by upstream kinases is required for activity in mammalian cells, Biochem. J. source

In the paper

“The α-subunit is essential, and a double knockout (KO) of AMPKα1 and AMPKα2 in mice gives rise to embryonic lethality [24].”

What the sources say

• Not checked yetcites [24] Viollet, 2009, AMPK: Lessons from transgenic and knockout animals, Front. Biosci. (Landmark Ed.) source

In the paper

“The α-subunit contains the kinase domain and a critical residue (Thr174 in α1-subunit and Thr172 in α2-subunit, hereafter referred to as Thr172) that is phosphorylated by upstream kinases [1].”

What the sources say

• Not checked yetcites [1] Hardie, 2012, AMPK: A nutrient and energy sensor that maintains energy homeostasis, Nat. Rev. Mol. Cell Biol. source

In the paper

“Liver kinase B 1 (LKB1) [32] and calcium/calmodulin-dependent protein kinase kinase (CAMKK) 2 [33,34] can be employed as the two main mammalian upstream molecules that phosphorylate AMPK.”

What the sources say

• Not checked yetcites [32] Woods, 2003, LKB1 is the upstream kinase in the AMP-activated protein kinase cascade, Curr. Biol. source
• Not checked yetcites [33] Fujiwara, 2016, Differential AMP-activated Protein Kinase (AMPK) Recognition mechanism of Ca2+/calmodulin-dependent protein kinase kinase isoforms, J. Biol. Chem. source
• Not checked yetcites [34] Hawley, 2005, Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase, Cell Metab. source

In the paper

“In H4IIEC3 cells, exogenous hydrogen peroxide transiently increased the level of phosphor-AMPK by LKB1 signaling, while exogenous hydrogen peroxide promoted AMPK phosphorylation in HeLa cells by CaMKK signaling [42].”

What the sources say

• Not checked yetcites [42] Liangpunsakul, 2008, Effect of ethanol on hydrogen peroxide-induced AMPK phosphorylation, Am. J. Physiol. Gastrointest. Liver Physiol. source

In the paper

“TPr agonists-activated AMPK was mediated by hydrogen peroxide, as demonstrated by the results showing overexpression of catalase (CAT) abolished Tpr agonists-induced AMPK activation [61].”

What the sources say

• Not checked yetcites [61] Zhang, 2008, Thromboxane receptor activates the AMP-activated protein kinase in vascular smooth muscle cells via hydrogen peroxide, Circ. Res. source

In the paper

“Exogenous or glucose oxidase-generated hydrogen peroxide induced direct S-glutathionylation on the AMPKα subunit at Cys299 and Cys304, which contributes to AMPK activation [48].”

What the sources say

• Not checked yetcites [48] Zmijewski, 2010, Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase, J. Biol. Chem. source

In the paper

“Its decrease occurs in response to lipid infiltration, oxidative stress, and inflammatory factors, which play a vital role in endothelial dysfunction [153].”

What the sources say

• Not checked yetcites [153] Chen, 2018, Nitric oxide bioavailability dysfunction involves in atherosclerosis, Biomed. Pharmacother. source

In the paper

“Additional evidence supporting AMPK protection against oxidative stress is that AMPK negatively regulates NOX by reducing its phosphorylation and preventing P47phox’s translocation to membrane [70,151].”

What the sources say

• Not checked yetcites [70] Wang, 2010, AMPKalpha2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: Role of 26S proteasomes, Circ. Res. source
• Not checked yetcites [151] McCarty, 2009, AMP-activated kinase may suppress NADPH oxidase activation in vascular tissues, Med. Hypotheses source

In the paper

“Moreover, the suppression of oxidative stress, in turn, blunted the activation of the protein kinase B-cyclic AMP-responsive element binding protein–PGC1α pathway, which ameliorated mitochondrial dysfunction and apoptosis [129].”

What the sources say

• Not checked yetcites [129] Ou, 2019, Fucoxanthin protects against oxLDL-induced endothelial damage via activating the AMPK-Akt-CREB-PGC1alpha pathway, Mol. Nutr. Food Res. source

In the paper

“Alternatively, some studies showed that ROS directly activated AMPK independent of changes in ADP, AMP, and ATP.”

In the paper

“AMPK suppresses protein kinase C activity and prevents protein kinase C modulation of p47phox phosphorylation [152].”

What the sources say

• Not checked yetcites [152] Ou, 2013, Ginkgo biloba extract attenuates oxLDL-induced endothelial dysfunction via an AMPK-dependent mechanism, J. Appl. Physiol. (1985) source

In the paper

“It is well established that the ROS-induced energy stress strongly activates AMPK, which is likely the main mechanism of ROS-mediated AMPK activation.”

In the paper

“Similarly, in NIH-3T3 cells, exogenous hydrogen peroxide transiently activated AMPK in a dose-dependent manner, which was associated with an increased AMP-to-ATP ratio [45].”

What the sources say

• Not checked yetcites [45] Choi, 2001, The regulation of AMP-activated protein kinase by H(2)O(2), Biochem. Biophys. Res. Commun. source

In the paper

“Vasculature I/R injury alleviates the efficiency of reperfusion therapy and compromises the clinical benefits of patients with acute MI [181].”

What the sources say

• Not checked yetcites [181] Ndrepepa, 2010, 5-year prognostic value of no-reflow phenomenon after percutaneous coronary intervention in patients with acute myocardial infarction, J. Am. Coll. Cardiol. source

In the paper

“However, with increasing mitochondria, the level of ROS is also increased as mitochondrial byproducts, which can result in oxidative damage of mitochondria [176].”

What the sources say

• Not checked yetcites [176] Fischer, 2012, Mitochondrial quality control: An integrated network of pathways, Trends Biochem. Sci. source

In the paper

“Mitochondria-targeted esculetin, capable of scavenging mitochondrial ROS, greatly alleviated angiotensin II-induced monocyte infiltration, atherosclerotic plaque formation, and serum pro-inflammatory cytokine production in apolipoprotein E KO mice [131].”

What the sources say

• Not checked yetcites [131] Karnewar, 2016, Mitochondria-targeted esculetin alleviates mitochondrial dysfunction by AMPK-mediated nitric oxide and SIRT3 regulation in endothelial cells: Potential implications in atherosclerosis, Sci. Rep. source

In the paper

“During early reperfusion, treatment with metformin augmented I/R-induced AMPK activation and significantly increased eNOS phosphorylation at ser1177 [183].”

What the sources say

• Not checked yetcites [183] Calvert, 2008, Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling, Diabetes source

In the paper

“The apoptosis induces endothelial swelling, microvascular spasms, and capillary obstruction, which slows or even stops microcirculation blood flow following reperfusion [179].”

What the sources say

• Not checked yetcites [179] Kloner, 1974, The “no-reflow” phenomenon after temporary coronary occlusion in the dog, J. Clin. Investig. source

In the paper

“These results suggest that AMPK participates in mitophagy regulation, which thereby provides a valuable therapeutic target for ischemic heart diseases.”

What the sources say

• Not checked yetcites [133] Zhang, 2018, AMPK activation serves a critical role in mitochondria quality control via modulating mitophagy in the heart under chronic hypoxia, Int. J. Mol. Med.

In the paper

“Similarly, in comparison with the WT cells, tube formation in mouse arterial endothelial cells isolated from either AMPKα1−/− or AMPKα2−/− mice was significantly impaired, exhibiting oxidative stress and reduced expression of UCP2.”

What the sources say

• Not checked yetcites [132] Xu, 2011, Impaired expression of uncoupling protein 2 causes defective postischemic angiogenesis in mice deficient in AMP-activated protein kinase alpha subunits, Arterioscler. Thromb. Vasc. Biol. source

In the paper

“Mitophagy increased significantly in cardiomyocytes exposed to hypoxic conditions, which was accompanied by AMPK activation [133].”

What the sources say

• Not checked yetcites [133] Zhang, 2018, AMPK activation serves a critical role in mitochondria quality control via modulating mitophagy in the heart under chronic hypoxia, Int. J. Mol. Med.

In the paper

“Under chronic hypoxia, PGC1α is upregulated, resulting in a subsequent increase of mitochondrial biogenesis [175].”

What the sources say

• Not checked yetcites [175] Zhu, 2010, Hypoxia induces PGC-1alpha expression and mitochondrial biogenesis in the myocardium of TOF patients, Cell Res. source

In the paper

“Treatment of cardiomyocytes with carvedilol augmented phosphorylation of AMPK and its downstream substrate ACC, and ameliorated hypoxia-induced impairment [182].”

What the sources say

• Not checked yetcites [182] Hu, 2019, The cardioprotective effects of carvedilol on ischemia and reperfusion injury by AMPK signaling pathway, Biomed. Pharmacother. source

In the paper

“Mechanically, AMPK increased glucose uptake and glucose transporter 4 translocation [171], decreased apoptosis, improved post-ischemic recovery, and limited myocardial infarction (MI) [172,173].”

What the sources say

• Not checked yetcites [172] Ma, 2010, Impaired macrophage migration inhibitory factor-AMP-activated protein kinase activation and ischemic recovery in the senescent heart, Circulation source
• Not checked yetcites [173] Russell, 2004, AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury, J. Clin. Investig. source

In the paper

“Consistently, when AMPK activation was blocked, mitophagy decreased as well, which subsequently gave rise to cardiomyocyte apoptosis [133].”

What the sources say

• Not checked yetcites [133] Zhang, 2018, AMPK activation serves a critical role in mitochondria quality control via modulating mitophagy in the heart under chronic hypoxia, Int. J. Mol. Med.

In the paper

“I/R injury causes myocardial damage and increases 30-day mortality rates [180].”

What the sources say

• Not checked yetcites [180] Abbate, 2008, No-reflow: The next challenge in treatment of ST-elevation acute myocardial infarction, Eur. Heart J. source

In the paper

“Mechanically, AMPK increased glucose uptake and glucose transporter 4 translocation [171], decreased apoptosis, improved post-ischemic recovery, and limited myocardial infarction (MI) [172,173].”

What the sources say

• Not checked yetcites [171] Miller, 2008, Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart, Nature source

In the paper

“In vitro mechanism studies showed that I/R triggered a DRP1-dependent mitochondrial fragmentation, which subsequently led to oligomerization of voltage-dependent anion channel 1, liberation of hexokinase 2, opening of mitochondrial permeability transition pore, upregulation of PINK1–PARKIN signaling, and eventual mitophagy-mediated cell death [134].”

What the sources say

• Not checked yetcites [134] Zhou, 2017, Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis, J. Pineal. Res. source

In the paper

“The mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) is a bioactive mitochondrial-derived peptide shown to activate the AMPK pathway and modulate metabolic homeostasis [193].”

What the sources say

• Not checked yetcites [193] Lee, 2015, The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance, Cell Metab. source

In the paper

“Further mechanism studies showed that nitrite activated protein kinase A, which in turn suppressed DRP1-dependent mitochondrial fission, augmented ΔΨm, and promoted superoxide production [135].”

What the sources say

• Not checked yetcites [135] Mo, 2014, Nitrite activates protein kinase A in normoxia to mediate mitochondrial fusion and tolerance to ischaemia/reperfusion, Cardiovasc. Res. source

In the paper

“Melatonin promoted cell survival via AMPKα activation, accompanied by phosphor-DRP1-S616 reduction and phosphor-DRP1-S637 elevation, which normalized mitochondrial fission [134].”

What the sources say

• Not checked yetcites [134] Zhou, 2017, Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis, J. Pineal. Res. source

In the paper

“Melatonin significantly decreased myocadiac infarction, improved cardiac function, normalized blood flow, and lowered microcirculation perfusion impairment [134].”

What the sources say

• Not checked yetcites [134] Zhou, 2017, Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis, J. Pineal. Res. source

In the paper

“Histological analysis revealed that administration of melatonin restored the endothelial barrier, promoted eNOS expression, decreased inflammatory cell infiltration, and lowered endothelial damage in cardiac microcirculation endothelial cells [134].”

What the sources say

• Not checked yetcites [134] Zhou, 2017, Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis, J. Pineal. Res. source

In the paper

“In parallel, phosphorylated AMPK increased and the expression of endothelin B (ETB) and angiotensin II receptor type 1 (AT1) receptors decreased after MOTS-c treatment [136].”

What the sources say

• Not checked yetcites [136] Wei, 2020, Mitochondrial-derived peptide MOTS-c attenuates vascular calcification and secondary myocardial remodeling via adenosine monophosphate-activated protein kinase signaling pathway, Cardiorenal. Med. source

In the paper

“These results indicate that TSPO regulates neointimal formation after vascular injury via stimulating VSMC proliferation and migration, which is likely dependent on AMPK suppression [137].”

What the sources say

• Not checked yetcites [137] Wu, 2020, TSPO ligands prevent the proliferation of vascular smooth muscle cells and attenuate neointima formation through AMPK activation, Acta Pharmacol. Sin. source

In the paper

“Neointimal hyperplasia narrows the luminal diameter, leading to decreased blood flow and recurrence of anginal symptoms [196].”

What the sources say

• Not checked yetcites [196] Schwartz, 1997, Perspectives series: Cell adhesion in vascular biology. Smooth muscle migration in atherosclerosis and restenosis, J. Clin. Investig. source

In the paper

“The prevention of mitochondrial fission further restored the interaction between voltage-dependent anion channel 1 and hexokinase 2, stopped mitochondrial permeability transition pore opening, and PINK1–PARKIN activation, ultimately blunting cell death [134].”

What the sources say

• Not checked yetcites [134] Zhou, 2017, Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis, J. Pineal. Res. source

In the paper

“The loss of AMPK activity is believed to be pro-hypertrophic because lines of molecular signaling pathways that control cell growth are attenuated by AMPK activation [197,198,199].”

What the sources say

• Not checked yetcites [197] Chan, 2008, Resveratrol inhibits cardiac hypertrophy via AMP-activated protein kinase and Akt, J. Biol. Chem. source
• Not checked yetcites [198] Chan, 2004, Activation of AMP-activated protein kinase inhibits protein synthesis associated with hypertrophy in the cardiac myocyte, J. Biol. Chem. source
• Not checked yetcites [199] Browne, 2004, Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2 kinase and to its phosphorylation at a novel site, serine 398, J. Biol. Chem. source

In the paper

“Moreover, ROS scavenging blocks AMPK activation and blunts nitrite-induced cardioprotection after H/R [135].”

What the sources say

• Not checked yetcites [135] Mo, 2014, Nitrite activates protein kinase A in normoxia to mediate mitochondrial fusion and tolerance to ischaemia/reperfusion, Cardiovasc. Res. source

In the paper

“In the meantime, DRP1-S616 phosphorylation was decreased, while DRP1-S637 phosphorylation was increased, ultimately leading to mitochondrial fission [229].”

What the sources say

• Not checked yetcites [229] Zhou, 2018, Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission, Redox Biol. source

In the paper

“However, some pharmacological AMPK activators, such as MK-8722 [203], cause cardiac hypertrophy, which is considered the main side effect of pharmacological pan-AMPK activation [17].”

What the sources say

• Not checked yetcites [203] Feng, 2018, Discovery of MK-8722: A systemic, direct pan-activator of amp-activated protein kinase, ACS Med. Chem. Lett. source
• Not checked yetcites [17] Myers, 2017, Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy, Science source

In the paper

“In failing heart samples from patients or TAC mice, the isoform of AMPKα shifted from α2 to α1, which is associated with reduced mitophagy and dysfunctional mitochondria [117].”

What the sources say

• Not checked yetcites [117] Wang, 2018, AMPKalpha2 protects against the development of heart failure by enhancing mitophagy via pink1 phosphorylation, Circ. Res. source

In the paper

“Clusterin, which exerts beneficial effects in ECs under diabetic conditions (both type 1 and type 2), inhibits mitochondrial fragmentation while activating AMPK [228].”

What the sources say

• Not checked yetcites [228] Ren, 2019, Clusterin ameliorates endothelial dysfunction in diabetes by suppressing mitochondrial fragmentation, Free Radic. Biol. Med. source

In the paper

“Consistently, SIRT5 ablation attenuated cardiac hypertrophy and cardiac dysfunction in the TAC model, which is accompanied by the reduction of ATP, increase of AMP-to-ATP ratio, and enhancement of AMPK activity [138].”

What the sources say

• Not checked yetcites [138] Zhang, M., Wu, J., Sun, R., Tao, X., Wang, X., Kang, Q., Wang, H., Zhang, L., Liu, P., and Zhang, J. (2019). SIRT5 deficiency suppresses mitochondrial ATP production and promotes AMPK activation in response to energy stress. PLoS ONE, 14. source

In the paper

“Endothelial dysfunction is attributed to many causes, including oxidative stress, chronic inflammation, and endothelium activation, in diabetes, which exhibits excessive free fatty acid (FFA), insulin resistance, and/or hyperglycemia [216,217].”

What the sources say

• Not checked yetcites [216] Zhang, 2012, The link between metabolic abnormalities and endothelial dysfunction in type 2 diabetes: An update, Basic Res. Cardiol. source
• Not checked yetcites [217] Kim, 2006, Reciprocal relationships between insulin resistance and endothelial dysfunction: Molecular and pathophysiological mechanisms, Circulation source

In the paper

“SIRT5 deficiency attenuated ATP production from mitochondrial ETC, increased the AMP-to-ATP ratio, and in turn activated AMPK in both cultured cells and hearts under the conditions of energy stress [138].”

What the sources say

• Not checked yetcites [138] Zhang, M., Wu, J., Sun, R., Tao, X., Wang, X., Kang, Q., Wang, H., Zhang, L., Liu, P., and Zhang, J. (2019). SIRT5 deficiency suppresses mitochondrial ATP production and promotes AMPK activation in response to energy stress. PLoS ONE, 14. source

In the paper

“Both the conditions of hyperlipidemia and hyperglycemia impair mitochondrial dynamics by shifting the balance to excessive mitochondrial fission, leading to mitochondrial ROS over production and ETC impairment [221,222,223].”

What the sources say

• Not checked yetcites [221] LaRocca, 2014, Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice, J. Physiol. source
• Not checked yetcites [222] Huang, 2018, The uremic toxin hippurate promotes endothelial dysfunction via the activation of Drp1-mediated mitochondrial fission, Redox Biol. source
• Not checked yetcites [223] Yu, 2006, Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology, Proc. Natl. Acad. Sci. USA source

In the paper

“Thus, this study unveils a crucial role of SIRT5 in controlling cellular energy metabolism by AMPK activation upon energy stress, which further confirms the cardioprotective role of AMPK in left ventricular hypertrophy under the stress of pressure overload [138].”

What the sources say

• Not checked yetcites [138] Zhang, M., Wu, J., Sun, R., Tao, X., Wang, X., Kang, Q., Wang, H., Zhang, L., Liu, P., and Zhang, J. (2019). SIRT5 deficiency suppresses mitochondrial ATP production and promotes AMPK activation in response to energy stress. PLoS ONE, 14. source

In the paper

“MAMs play a vital role in lipid transport, Ca2+ signaling, cell survival, and energy metabolism [234], and have been implicated in diseases including Alzheimer’s disease [235], cancer [236], lysosomal storage disease [237], diabetes mellitus [238,239], obesity, and metabolic disorders [240].”

What the sources say

• Not checked yetcites [234] Rowland, 2012, Endoplasmic reticulum-mitochondria contacts: Function of the junction, Nat. Rev. Mol. Cell Biol. source
• Not checked yetcites [235] Suski, 2017, Localization and processing of the amyloid-beta protein precursor in mitochondria-associated membranes, J. Alzheimers Dis.
• Not checked yetcites [236] Ando, 2018, Remodeling of Ca(2+) signaling in cancer: Regulation of inositol 1,4,5-trisphosphate receptors through oncogenes and tumor suppressors, Adv. Biol. Regul. source

In the paper

“High glucose-driven inactivation of AMPK increased FUNDC1, resulting in aberrant MAM formation, mitochondrial Ca2+ increase, mitochondrial dysfunction, and cardiac dysfunction [139].”

What the sources say

• Not checked yetcites [139] Wu, 2019, Hyperglycemia-Driven Inhibition of AMP-activated protein kinase alpha2 induces diabetic cardiomyopathy by promoting mitochondria-associated endoplasmic reticulum membranes in vivo, Circulation source

In the paper

“Upregulation of XO was accompanied by excessive ROS production, resulting in the Ser616 phosphorylation as well as the mitochondrial migration of DRP1 [140].”

What the sources say

• Not checked yetcites [140] Cui, 2018, Melatonin alleviates inflammation-induced apoptosis in human umbilical vein endothelial cells via suppression of Ca(2+)-XO-ROS-Drp1-mitochondrial fission axis by activation of AMPK/SERCA2a pathway, Cell Stress Chaperones source

In the paper

“Vildagliptin improved mitochondrial dysfunction in diabetic ECs, possibly by blunting DRP1-dependent mitochondrial fission by inducing AMPK activation [230].”

What the sources say

• Not checked yetcites [230] Liu, 2019, Vildagliptin improves high glucose-induced endothelial mitochondrial dysfunction via inhibiting mitochondrial fission, J. Cell. Mol. Med. source

In the paper

“Thus, under diabetic conditions, ECs often have reduced eNOS activity and diminished NO production [259].”

What the sources say

• Not checked yetcites [259] Dresner, 1999, Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity, J. Clin. Investig. source

In the paper

“Importantly, melatonin activated AMPK, which was associated with the upregulation of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a [140].”

What the sources say

• Not checked yetcites [140] Cui, 2018, Melatonin alleviates inflammation-induced apoptosis in human umbilical vein endothelial cells via suppression of Ca(2+)-XO-ROS-Drp1-mitochondrial fission axis by activation of AMPK/SERCA2a pathway, Cell Stress Chaperones source

In the paper

“Obesity-related type 2 diabetes patients often have elevated plasma FFAs, because of either increased amounts of FFAs released from large amounts of adipose tissue or impaired FFA clearance [258].”

What the sources say

• Not checked yetcites [258] Boden, 2003, Effects of free fatty acids (FFA) on glucose metabolism: Significance for insulin resistance and type 2 diabetes, Exp. Clin. Endocrinol. Diabetes source

In the paper

“Further, melatonin-activated AMPK-sarcoplasmic/endoplasmic reticulum calcium ATPase 2a axis prevented calcium overload, XO-dependent ROS overproduction, DRP1-mediated mitochondrial fission, and apoptosis in lipopolysaccharide-treated cells [140].”

What the sources say

• Not checked yetcites [140] Cui, 2018, Melatonin alleviates inflammation-induced apoptosis in human umbilical vein endothelial cells via suppression of Ca(2+)-XO-ROS-Drp1-mitochondrial fission axis by activation of AMPK/SERCA2a pathway, Cell Stress Chaperones source

In the paper

“Lipopolysaccharide triggered cytosolic calcium overload, and in turn upregulated XO, whose activity is calcium-dependent [140].”

What the sources say

• Not checked yetcites [140] Cui, 2018, Melatonin alleviates inflammation-induced apoptosis in human umbilical vein endothelial cells via suppression of Ca(2+)-XO-ROS-Drp1-mitochondrial fission axis by activation of AMPK/SERCA2a pathway, Cell Stress Chaperones source

In the paper

“Study showed that mitochondrial outer membrane protein FUN14 domain containing 1 (FUNDC1) is essential for maintaining the MAM structure and ensuring appropriate Ca2+ transfer from the sarcoplasmic reticulum (i.e., ER in myocytes) to mitochondria in healthy hearts [241].”

What the sources say

• Not checked yetcites [241] Wu, 2017, Binding of FUN14 domain containing 1 with inositol 1,4,5-trisphosphate receptor in mitochondria-associated endoplasmic reticulum membranes maintains mitochondrial dynamics and function in hearts in vivo, Circulation source

In the paper

“CRA activated AMPK in a LKB1-dependent manner, and AMPK silencing abrogated its inhibitory effect on DRP1 activation and mitochondrial fission [141].”

What the sources say

• Not checked yetcites [141] Li, 2016, Inhibition of mitochondrial fission and NOX2 expression prevent nlrp3 inflammasome activation in the endothelium: The role of corosolic acid action in the amelioration of endothelial dysfunction, Antioxid. Redox Signal. source

In the paper

“DRP1 knockdown attenuated PA-induced NOX2 activation, and knockdown of DRP1 or NOX2 suppressed PA-induced NACHT, LRR, and PYD domains-containing protein 3 inflammatory effect and, in the meantime, strengthened the inhibitory effects of CRA [141].”

What the sources say

• Not checked yetcites [141] Li, 2016, Inhibition of mitochondrial fission and NOX2 expression prevent nlrp3 inflammasome activation in the endothelium: The role of corosolic acid action in the amelioration of endothelial dysfunction, Antioxid. Redox Signal. source

In the paper

“Obesity is closely associated with cardiac disorders, which is assumed to be a consequence of the adaption to an oversupply of high-fat substrates [262,263].”

What the sources say

• Not checked yetcites [262] Harmancey, 2008, Adaptation and maladaptation of the heart in obesity, Hypertension source
• Not checked yetcites [263] Louwe, 2012, Gender-dependent effects of high-fat lard diet on cardiac function in C57Bl/6J mice, Appl. Physiol. Nutr. Metab. source

In the paper

“It is well-accepted that AMPK activation plays protective roles across diverse CVDs.”

In the paper

“These data collectively demonstrated that CRA prevented mitochondrial fission by regulating DRP1 phosphorylation at Ser637 in an AMPK-dependent manner, contributing to the blockage of NOX2-related oxidative stress and suppressing NACHT, LRR, and PYD domains-containing protein 3 inflammasome in the endothelium [141].”

What the sources say

• Not checked yetcites [141] Li, 2016, Inhibition of mitochondrial fission and NOX2 expression prevent nlrp3 inflammasome activation in the endothelium: The role of corosolic acid action in the amelioration of endothelial dysfunction, Antioxid. Redox Signal. source

In the paper

“Far beyond our current knowledge are the structural and functional changes to mitochondria that may be amplified under disease conditions.”

In the paper

“AMPK has emerged as a guardian of mitochondria because almost all mitochondrial insults can activate AMPK.”

In the paper

“However, the interplay within the AMPK–mitochondrial axis during the initiation and progression of CVDs is poorly investigated.”

In the paper

“Concomitantly, pomegranate extract activated AMPK, which may be responsible for the intervention of mitochondrial loss through promoting mitochondrial biogenesis and the attenuation of oxidative stress by means of upregulating phase II enzymes in HFD hearts [142].”

What the sources say

• Not checked yetcites [142] Cao, 2015, Punicalagin, an active component in pomegranate, ameliorates cardiac mitochondrial impairment in obese rats via AMPK activation, Sci. Rep. source

In the paper

“A direct functional connection between AMPK signaling and β-adrenergic responsiveness exists in the heart, and AMPK might be a valuable target to recover the decreased β-adrenergic responsive in the heart of obesity [270].”

What the sources say

• Not checked yetcites [270] Bussey, 2018, Cardiac beta-adrenergic responsiveness of obese Zucker rats: The role of AMPK, Exp. Physiol. source

In the paper

“Limited evidence has focused on mitochondrial dynamics, mitochondrial biogenesis, and mitophagy, the three common functions of mitochondria that have been studied by cell biologists.”

In the paper

“Punicalagin, the major active component in pomegranate extract, protects against HFD-induced cardiac disorders by activating AMPK pathway and promoting mitochondrial biogenesis [142].”

What the sources say

• Not checked yetcites [142] Cao, 2015, Punicalagin, an active component in pomegranate, ameliorates cardiac mitochondrial impairment in obese rats via AMPK activation, Sci. Rep. source

In the paper

“The loss of AMPK activity exacerbated cardiac hypertrophy and dysfunctional contractility of HFD-fed mice [268].”

What the sources say

• Not checked yetcites [268] Turdi, 2011, Deficiency in AMP-activated protein kinase exaggerates high fat diet-induced cardiac hypertrophy and contractile dysfunction, J. Mol. Cell. Cardiol. source

In the paper

“C1q/tumor necrosis factor-related protein 9 exhibited anti-myocardial lipotoxicity effects and attenuated cardiac hypertrophy, likely via activation of the LKB1–AMPK signaling [269].”

What the sources say

• Not checked yetcites [269] Zuo, 2020, CTRP9 knockout exaggerates lipotoxicity in cardiac myocytes and high-fat diet-induced cardiac hypertrophy through inhibiting the LKB1/AMPK pathway, J. Cell. Mol. Med. source

In the paper

“Increased body weight switches the substrate of the heart from fatty acid to sugar, resulting in fat accumulation around the heart and eventually inducing cardiac impairment and increasing the risk of MI [264,265].”

What the sources say

• Not checked yetcites [264] Schram, 2008, Implications of myocardial matrix remodeling by adipokines in obesity-related heart failure, Trends Cardiovasc. Med. source
• Not checked yetcites [265] Look, 2009, Adipocyte fatty acid-binding protein suppresses cardiomyocyte contraction: A new link between obesity and heart disease, Circ. Res. source