Modulation of mononuclear phagocyte inflammatory response by liposome-encapsulated voltage gated sodium channel inhibitor ameliorates myocardial ischemia/reperfusion injury in rats.
BACKGROUND
Emerging evidence shows that anti-inflammatory strategies targeting inflammatory monocyte subset could reduce excessive inflammation and improve cardiovascular outcomes. Functional expression of voltage-gated sodium channels (VGSCs) have been demonstrated in monocytes and macrophages. We hypothesized that mononuclear phagocyte VGSCs are a target for monocyte/macrophage phenotypic switch, and liposome mediated inhibition of mononuclear phagocyte VGSC may attenuate myocardial ischemia/reperfusion (I/R) injury and improve post-infarction left ventricular remodeling.


RESULTS
Thin film dispersion method was used to prepare phenytoin (PHT, a non-selective VGSC inhibitor) entrapped liposomes. Pharmacokinetic study revealed that the distribution and elimination half-life of PHT entrapped liposomes were shorter than those of free PHT, indicating a rapid uptake by mononuclear phagocytes after intravenous injection. In rat peritoneal macrophages, several VGSC α subunits (NaV1.1, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaVX, Scn1b, Scn3b and Scn4b) and β subunits were expressed at mRNA level, and PHT could suppress lipopolysaccharide induced M1 polarization (decreased TNF-α and CCL5 expression) and facilitate interleukin-4 induced M2 polarization (increased Arg1 and TGF-β1 expression). In vivo study using rat model of myocardial I/R injury, demonstrated that PHT entrapped liposome could partially suppress I/R injury induced CD43+ inflammatory monocyte expansion, along with decreased infarct size and left ventricular fibrosis. Transthoracic echocardiography and invasive hemodynamic analysis revealed that PHT entrapped liposome treatment could attenuate left ventricular structural and functional remodeling, as shown by increased ejection fraction, reduced end-systolic and end-diastolic volume, as well as an amelioration of left ventricular systolic (+dP/dt max) and diastolic (-dP/dt min) functions.


CONCLUSIONS
Our work for the first time demonstrates the therapeutic potential of VGSC antagonism via liposome mediated monocyte/macrophage targeting in acute phase after myocardial I/R injury. These results suggest that VGSCs in mononuclear phagocyte system might be a novel target for immunomodulation and treatment of myocardial I/R injury.
Institute of Cardiovascular Disease and Heart Center, Pingjin Hospital, Logistics University of the Chinese People's Armed Police Forces, Tianjin, China ; Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Tianjin, China.
Xin
X
Zhou
Yue-Chen
YC
Luo
Wen-Jie
WJ
Ji
Li
L
Zhang
Yan
Y
Dong
Lan
L
Ge
Rui-Yi
RY
Lu
Hai-Ying
HY
Sun
Zao-Zeng
ZZ
Guo
Guo-Hong
GH
Yang
Tie-Min
TM
Jiang
Yu-Ming
YM
Li
D000818:Animals; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006439:Hemodynamics; D015847:Interleukin-4 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology; D008081:Liposomes; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010586:Phagocytes / Q000187:drug effects* / Q000378:metabolism*; D010672:Phenytoin / Q000008:administration & dosage; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling; D061567:Voltage-Gated Sodium Channel Blockers / Q000008:administration & dosage*; D061566:Voltage-Gated Sodium Channels / Q000235:genetics / Q000378:metabolism*
D008070:Lipopolysaccharides; D008081:Liposomes; D012333:RNA, Messenger; D061567:Voltage-Gated Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; D015847:Interleukin-4; D010672:Phenytoin