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Review
. 2024 Jan 20;25(2):1290.
doi: 10.3390/ijms25021290.

High-Density Lipoproteins at the Interface between the NLRP3 Inflammasome and Myocardial Infarction

Helison R P Carmo  1 , Isabella Bonilha  1 , Joaquim Barreto  1 , Massimiliano Tognolini  2 , Ilaria Zanotti  2 , Andrei C Sposito  1
Affiliations
Review

High-Density Lipoproteins at the Interface between the NLRP3 Inflammasome and Myocardial Infarction

Helison R P Carmo et al. Int J Mol Sci. .

Abstract

Despite significant therapeutic advancements, morbidity and mortality following myocardial infarction (MI) remain unacceptably high. This clinical challenge is primarily attributed to two significant factors: delayed reperfusion and the myocardial injury resulting from coronary reperfusion. Following reperfusion, there is a rapid intracellular pH shift, disruption of ionic balance, heightened oxidative stress, increased activity of proteolytic enzymes, initiation of inflammatory responses, and activation of several cell death pathways, encompassing apoptosis, necroptosis, and pyroptosis. The inflammatory cell death or pyroptosis encompasses the activation of the intracellular multiprotein complex known as the NLRP3 inflammasome. High-density lipoproteins (HDL) are endogenous particles whose components can either promote or mitigate the activation of the NLRP3 inflammasome. In this comprehensive review, we explore the role of inflammasome activation in the context of MI and provide a detailed analysis of how HDL can modulate this process.

Keywords: HDL; NLRP3 inflammasome; ischemia-reperfusion injury; myocardial infarction.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Minutes/hours from MI and hours/days from MI. The NLRP3 inflammasome cellular mechanism initiates during the first minutes of MI and can persist for days, exerting an influence on acute or chronic outcomes. Activation of pro-IL-1β and pro-IL18 and their respective release outside the membrane (I); gasdermin-D on the lytic cell death due to the pore formation on the cellular membrane, characterized by proinflammatory cell death or pyroptosis (II); proinflammatory oxidized LDL (III); TLR4 and NLRP3 inflammasome transcription pathway (IV); MI exacerbates the production of mitochondrial ROS in a process mediated by the TXNIP (V); P2X7R receptor under ATP stimulation promotes calcium and sodium influx, resulting in potassium efflux and classic signaling for NLRP3 inflammasome activation (VI); ionic imbalance (mainly by increase of Ca2+ mobilization and decrease of K+ efflux) (VII); endoplasmic reticulum stress, triggering caspase 4/5/11 activation (VIII); Cathepsin B, inducing NLRP3 activation (VIX); S1PRs play a crucial role in the interaction of S1P, facilitating cytoprotective mechanisms both short- and long-term, following MI (X and XI). The activation of the Tumor Necrosis Factor 2 Receptor (TRAF2) by HDL can influence the activity of sphingosine kinase-1 and consequently increase the production of sphingosine-1-phosphate (XII). The arrows mean the increase (↑) or decrease (↓) in ion concentration into the cytoplasmic milieu.
Figure 2
Figure 2
Representative image of isolated perfused hearts (ex vivo) using Langendorff apparatus undergoing ischemia and reperfusion protocol. Rat heart during regional ischemia (A1) and reperfusion (A2). Figures represent groups that received vehicle (B1) or HDL (200 µg/mL) infusion (B2), after the protocol of staining with 2,3,5-triphenyltetrazolium chloride staining. The heart sections (B1,B2) are presented in tree colors for histologic analysis: blue, the non-ischemic area (also known as non-risk area); red, the ischemic area (also known as area-at-risk); and white or pale, the infarct area. The infarct size was calculated as a percentage of the area-at-risk.
Figure 3
Figure 3
HDL receptors of cardioprotective protein kinase pathways. Representative signaling mediated by HDL through the reperfusion salvage kinase (RISK) pathway and the survivor-activating factor enhancement (SAFE) pathway. The arrows represent stimulation, while the hammerheads represent inhibition.
Figure 4
Figure 4
A schematic representation of HDL triggering NLRP3 activation signaling. The role of HDL in the context of myocardial infarction is illustrated along the six pivotal steps, culminating in NLRP3 activation signaling and the ultimate myocardial damage. HDL complement acronyms that could participate in the remodeling process: apolipoprotein A-I (ApoA-I); apolipoprotein A-II (ApoA-II); apolipoprotein A-V (ApoA-V); apolipoprotein C-I (ApoC-I); apolipoprotein C-III (ApoC-III); apolipoprotein C-IV (ApoC-IV); apolipoprotein D (ApoD); apolipoprotein E (ApoE); apolipoprotein F (ApoF); apolipoprotein J (ApoJ); apolipoprotein M (ApoM); apolipoprotein H (ApoH); apolipoprotein O (ApoO); apolipoprotein (ApoL-I); cholesteryl ester transfer protein (CETP); phospholipid transfer protein (PLTP); lecithin cholesterol acyltransferase (LCAT); paraoxonase-1 (PON1); paraoxonase-1 (PON3); serum amyloid A (SAA); serum amyloid A-2 (SAA2); serum amyloid A-4 (SAA4); Sphingomyelin (SM); Sphingosine 1-phosphate (S1P); microRNA (miRNas); and reactive oxygen species (ROS). ↑ means increase; ↓ means decrease.
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