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Miura et al. Vessel Plus 2019;3:1 I http://dx.doi.org/10.20517/2574-1209.2018.69 Page 5 of 15

The proatherogenic mechanisms associated with TG and TGRL are rather complicated and need to be
further explored. However, current knowledge and accumulating evidences of clinical studies indicate
that therapies lowering TG levels can be one of important treatment strategies to suppress atherosclerotic
formation and ischemic stroke risks.

High-density lipoprotein Cho
High-density lipoprotein Cho (HDL-C) is potentially highly protective for atherosclerosis. HDL-C is
classically known to reverse Cho transport: that is, HDL-C removes excess Cho from foam cells within
[41]
peripheral tissues, and delivers it to liver for metabolism . In addition, recent reports have shown that
HDL-C exerts a lot of other functions, which reduce atherosclerotic development [41-43] . Beneficial effects
of HDL-C against atherogenesis may come from its protective effects against the generation of reactive
[42]
oxygen species and VCAMs . Reconstituted HDL-C suppresses the activation of leukocyte NADPH
[43]
oxidases . The effects of HDL-C may contribute to protecting vascular injuries, resulting in the suppression
of atherosclerosis. HDL-C inhibits the expressions of cytokine-induced CAMs, and then suppresses the
[44]
adhesion of monocytes to ECs . Paraoxonase-containing HDL-C suppresses oxidation of LDL-C, and
[45]
prevents expressions of monocyte chemotactic protein-1 . As well, LDL-C was reported to increase
monocyte chemotactic protein-1 expressions and cause 7-fold increases in monocyte migration into the
[46]
subendothelial space, whereas purified HDLs inhibited the monocyte migration by 91% .

HDL-C protects erythrocytes against the generation of procoagulant activity, and enhances anticoagulant
[47]
activities of protein S . HDL-C is also positively correlated with plasminogen activator inhibitor-1
[21]
activity . Furthermore, HDL-C inhibits thrombin-induced binding of fibrinogen to platelets and suppresses
[48]
the platelet aggregation . Thus, HDL-C can reduce blood clot formation, and therefore high levels of
HDL-C can prevent ischemic stroke.

DYSLIPIDEMIA AND STROKE
A high level of serum total Cho (TC) and LDL-C is well known to be major risk factors for ischemic stroke.
LDL-C-lowering therapies have attracted extensive attention, and have been a cornerstone of the primary
[49]
and secondary prevention for ischemic stroke . Recently, higher TG levels also have been repeatedly
[50]
reported to increase atherosclerotic risks . A meta-analysis study was conducted to investigate the
association between lipid levels induced by lipid-modifying drugs and stroke risks, and revealed that higher
levels of TG at baseline had a higher incidence of ischemic stroke occurrence (adjusted relative risk, 1.05
[50]
per 10 mg/dL increase) in placebo groups in 64 randomized clinical trials . In contrast, HDL-C levels are
inversely associated with risks for the development of atherosclerosis and ischemic stroke [41,51,52] . According
to a systematic review of 18 prospective studies investigating relationships between HDL-C levels and stroke
[52]
risks, each 10 mg/dL increase in HDL-C levels decreased risks for ischemic strokes ranging from 11%-15% .
Some reports suggested that the negative association between HDL-C levels and ischemic stroke risks is
more dependent on HDL-C sub-fractions rather than total levels of HDL-C. HDL sub-fractions have been
classified on their size and relative concentrations of Cho, and each sub-fraction is known to have different
biological activities, biochemical properties, and vascular metabolisms [41,53] . HDL-2 and HDL-3 are major
[53]
circulating sub-fractions in the peripheral blood . In contrast with HDL-2, smaller dense protein-rich
[53]
HDL-3 appears to suppress oxidation of LDLs and thereby to prevent atherosclerosis . It was demonstrated
that HDL sub-fractions differently influenced CA diseases in the Northern Manhattan study: HDL-2 and
[54]
plaque thickness were positively related, while HDL-3 and plaque area were inversely associated . In
another prospective study, however, small-size HDL-C and medium-size HDL-C were both associated
[55]
with lower incidences of stroke occurrence, in particular as to lacunar infarcts and hemorrhagic strokes .
[55]
On the other hand, large-size HDL-C did not influence the stroke risks . More studies are thus needed
to clarify and understand the association between HDL sub-fractions and the risk of strokes. Another
important finding is that lower levels of TC and LDL-C were associated with higher risks of intracranial