Lipoproteins in Cardiovascular Calcification: Potential Targets and Challenges

Tintut, Yin; Hsu, Jeffrey J.; Demer, Linda L.

doi:10.3389/fcvm.2018.00172

Cited by 30 publications

(29 citation statements)

References 135 publications

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“…Their data approved that atorvastatin can protect VSMC differentiation from TGF-β1-stimulated calcification through suppression of β-catenin pathway [ 35 ]. Their data are consistent with the recently results that atorvastatin could reduce arterial calcification and plasma calcium concentration [ 45 ] (Fig. 1 ).…”

Section: Autophagy Affects Vascular Calcification By Interfering With the Osteogenic Differentiation Of Vsmcssupporting

confidence: 93%

Multiple functions of autophagy in vascular calcification

Zhou

Yuan

et al. 2021

Cell Biosci

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Background Vascular calcification is a closely linked to cardiovascular diseases, such as atherosclerosis, chronic kidney disease, diabetes, hypertension and aging. The extent of vascular calcification is closely correlate with adverse clinical events and cardiovascular all-cause mortality. The role of autophagy in vascular calcification is complex with many mechanistic unknowns. Methods In this review, we analyze the current known mechanisms of autophagy in vascular calcification and discuss the theoretical advantages of targeting autophagy as an intervention against vascular calcification. Results Here we summarize the functional link between vascular calcification and autophagy in both animal models of and human cardiovascular disease. Firstly, autophagy can reduce calcification by inhibiting the osteogenic differentiation of VSMCs related to ANCR, ERα, β-catenin, HIF-1a/PDK4, p62, miR-30b, BECN1, mTOR, SOX9, GHSR/ERK, and AMPK signaling. Conversely, autophagy can induce osteoblast differentiation and calcification as mediated by CREB, degradation of elastin, and lncRNA H19 and DUSP5 mediated ERK signaling. Secondly, autophagy also links apoptosis and vascular calcification through AMPK/mTOR/ULK1, Wnt/β-catenin and GAS6/AXL synthesis, as apoptotic cells become the nidus for calcium-phosphate crystal deposition. The failure of mitophagy can activate Drp1, BNIP3, and NR4A1/DNA‑PKcs/p53 mediated intrinsic apoptotic pathways, which have been closely linked to the formation of vascular calcification. Additionally, autophagy also plays a role in osteogenesis by regulating vascular calcification, which in turn regulates expression of proteins related to bone development, such as osteocalcin, osteonectin, etc. and regulated by mTOR, EphrinB2 and RhoA. Furthermore, autophagy also promotes vitamin K2-induced MC3T3 E1 osteoblast differentiation and FGFR4/FGF18- and JNK/complex VPS34–beclin-1-related bone mineralization via vascular calcification. Conclusion The interaction between autophagy and vascular calcification are complicated, with their interaction affected by the disease process, anatomical location, and the surrounding microenvironment. Autophagy activation in existent cellular damage is considered protective, while defective autophagy in normal cells result in apoptotic activation. Identifying and maintaining cells at the delicate line between these two states may hold the key to reducing vascular calcification, in which autophagy associated clinical strategy could be developed.

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Section: Autophagy Affects Vascular Calcification By Interfering With the Osteogenic Differentiation Of Vsmcssupporting

confidence: 93%

Multiple functions of autophagy in vascular calcification

Zhou

Yuan

et al. 2021

Cell Biosci

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“…Apart from being an established cardiovascular risk factor, Lp(a) recently emerged as a potential biomarker for CAC volume progression [ 46 ]. Moreover, earlier studies demonstrated positive correlation between Lp(a) and MGP levels hypothesizing that the high levels of MGP associated with Lp(a) are owing to a negative feedback loop [ 47 , 48 ]. In addition, Lp(a) also emerged as a viable therapeutic target since it has been shown that it may significantly contribute to residual cardiovascular risk in patients with CAD and optimal LDL-C levels [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Circulating Levels of Dephosphorylated-Uncarboxylated Matrix Gla Protein in Patients with Acute Coronary Syndrome

et al. 2021

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Vascular calcification contributes to the pathogenesis of coronary artery disease while matrix Gla protein (MGP) was recently identified as a potent inhibitor of vascular calcification. MGP fractions, such as dephosphorylated-uncarboxylated MGP (dp-ucMGP), lack post-translational modifications and are less efficient in vascular calcification inhibition. We sought to compare dp-ucMGP levels between patients with acute coronary syndrome (ACS), stratified by ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) status. Physical examination and clinical data, along with plasma dp-ucMGP levels, were obtained from 90 consecutive ACS patients. We observed that levels of dp-ucMGP were significantly higher in patients with NSTEMI compared to STEMI patients (1063.4 ± 518.6 vs. 742.7 ± 166.6 pmol/L, p < 0.001). NSTEMI status and positive family history of cardiovascular diseases were only independent predictors of the highest tertile of dp-ucMGP levels. Among those with NSTEMI, patients at a high risk of in-hospital mortality (adjudicated by GRACE score) had significantly higher levels of dp-ucMGP compared to non-high-risk patients (1417.8 ± 956.8 vs. 984.6 ± 335.0 pmol/L, p = 0.030). Altogether, our findings suggest that higher dp-ucMGP levels likely reflect higher calcification burden in ACS patients and might aid in the identification of NSTEMI patients at increased risk of in-hospital mortality. Furthermore, observed dp-ucMGP levels might reflect differences in atherosclerotic plaque pathobiology between patients with STEMI and NSTEMI.

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“…PCSK9 inhibitors attenuate local vascular inflammation and accelerate plaque delipidation when added to statins [ 37 ]. However, unlike statins, PCSK9 inhibitors have the benefit of lowering lipoprotein (a), a lipoprotein known to potentiate vascular calcification [ 38 , 39 ]. Macrocalcifications are best visualized on cardiac-gated CT imaging without contrast.…”

Section: Inflammation and The Pathobiology Of Atherosclerosismentioning

confidence: 99%

Inflammation and cardiovascular disease: From mechanisms to therapeutics

Alfaddagh

Martin

Leucker

et al. 2020

American Journal of Preventive Cardiology

202

108

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Inflammation constitutes a complex, highly conserved cascade of molecular and cellular events. Inflammation has been labeled as “the fire within,” is highly regulated, and is critical to host defense and tissue repair. In general, inflammation is beneficial and has evolved to promote survival. However, inflammation can also be maladaptive when chronically activated and sustained, leading to progressive tissue injury and reduced survival. Examples of a maladaptive response include rheumatologic disease and atherosclerosis. Despite evidence gathered by Virchow over 100 years ago showing that inflammatory white cells play a role in atherogenesis, atherosclerosis was until recently viewed as a disease of passive cholesterol accumulation in the subendothelial space. This view has been supplanted by considerable basic scientific and clinical evidence demonstrating that every step of atherogenesis, from the development of endothelial cell dysfunction to foam cell formation, plaque formation and progression, and ultimately plaque rupture stemming from architectural instability, is driven by the cytokines, interleukins, and cellular constituents of the inflammatory response. Herein we provide an overview of the role of inflammation in atherosclerotic cardiovascular disease, discuss the predictive value of various biomarkers involved in inflammation, and summarize recent clinical trials that evaluated the capacity of various pharmacologic interventions to attenuate the intensity of inflammation and impact risk for acute cardiovascular events.

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Lipoproteins in Cardiovascular Calcification: Potential Targets and Challenges

Cited by 30 publications

References 135 publications

Multiple functions of autophagy in vascular calcification

Multiple functions of autophagy in vascular calcification

Circulating Levels of Dephosphorylated-Uncarboxylated Matrix Gla Protein in Patients with Acute Coronary Syndrome

Inflammation and cardiovascular disease: From mechanisms to therapeutics

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