PDZK1 in leukocytes protects against cellular apoptosis and necrotic core development in atherosclerotic plaques in high fat diet fed ldl receptor deficient mice

Abstract

PDZK1 is required for anti-atherogenic responses in macrophages including HDL dependent protection against apoptosis and macrophage mediated efferocytosis and limits the accumulation of apoptotic cells within atherosclerotic plaques protecting against necrotic core development.

Beyond cholesterol homeostasis: A novel role for PDZK1 in macrophage apoptosis and atherosclerosis

“…This study by Yu et al [4], along with many recent in vitro and pre-clinical animal studies, highlights the multi-facet beneficial actions of HDL, beyond cholesterol transport, in mediating atheroprotection. Moreover, decades of epidemiological evidence show that low levels of circulating HDL correlated with increased atherosclerotic disease.…”

“…In conclusion, the study by Yu and colleagues [4,9] identify for the first time a new role for macrophage PDZK1 in protecting against apoptosis and promoting macrophage migration, ultimately reducing atherosclerotic progression. These studies have identified additional mechanisms that regulate macrophage cell death and how HDL can protect against macrophage apoptosis.…”

“…Macrophage SR-BI binds to the exposed phosphatidylserine (PS) on apoptotic cells to mediate the efficient engulfment and internalisation of these apoptotic bodies in a Src/PI3K/Rac1-dependent manner [13]. Interestingly, in contrast, Yu et al [4] found that the absence of PDZK1 or the addition of HDL did not influence the efficient efferocytosis by macrophage, suggesting that SR-BI binding to PS and internalization into the phagosome are differentially regulated and occur independently of the adaptor protein, PDZK1 and HDL-signalling. Although HDL does not appear to impact efferocytosis per se, it has been shown to protect against efferocyte apoptosis by reducing inflammatory NADPH oxidase-Nox2 signalling in a cholesterol transporter (ABCA1, ABCG1)-dependent manner [14].…”

“…In this issue of Atherosclerosis, Yu et al investigate the role of leukocyte-specific PDZK1 in apoptosis and atherosclerosis for the first time [4]. PDZK1 is an adaptor protein that has been previously been shown to stabilize SR-B1 protein expression in the liver (but not in bone marrow cells) [5,6].…”

“…While it has been shown that HDL signalling through PDZK1/SR-B1 in macrophages promotes chemotaxis in vitro [9], the role of PDZK1 in regulating macrophage function in vivo and how that directly impacts atherosclerosis is unknown. To this end, Yu and colleagues irradiated and transplanted atherosclerotic prone Ldlr À/À with PDZK1 deficient or wild-type (WT) bone-marrow cells [4]. After 10 weeks of high fat diet, the authors showed that the deletion of PDZK1 in bone marrow cells promoted lesional macrophage apoptosis, increased necrotic core area and the development of large, complex atherosclerotic lesions.…”