Brian Rodrigues

In Canada, more than 11 million individuals live with diabetes or pre-diabetes. Heart failure, a leading cause of death in this disease, can result from an intrinsic malfunction of the cardiac muscle (diabetic cardiomyopathy; DCM). The etiology of DCM is complex, with changes in cardiac metabolism (reduced glucose but greater fatty acid (FA) consumption), a major culprit. This leads to a mismatch between FA delivery and utilization, leading to lipid metabolite build-up and cell death. In this milieu, protection against excessive accumulation of the precursors of triglyceride, FA or their metabolites in the diabetic heart would be advantageous. Strategies to do this include improving insulin sensitivity to lower FA uptake and/or enhancing FA oxidation in cardiomyocyte mitochondria. Vascular endothelial growth factor (VEGF) B is unique in its ability to a) enhance VEGFA-induced angiogenesis, b) trigger metabolic reprogramming and c) inhibit cell death. In hearts overexpressing VEGFB, its known angiogenic response was associated with an augmentation of cardiac insulin action. Additionally, multiple regulatory mechanisms lowered coronary lipoprotein lipase (LPL) and was accompanied by reduced cardiac lipid metabolite accumulation. With overnight fasting and reduced circulating insulin, VEGFB acts unimpeded, such that cardiac LPL-derived FA uptake took precedence over non-esterified fatty acids. Nevertheless, an augmented mitochondrial oxidation prevented lipid accumulation in the heart, highlighting the potential for VEGFB to protect against lipotoxicity. Diabetes had multiple effects on VEGFB biology, including a reduction in gene expression, protein secretion and receptor signaling. Thus, loss of VEGFB action may contribute to metabolic inflexibility and lipotoxicity, key contributors towards development of the cardiovascular complications seen during diabetes. As mechanism-directed therapeutic care for DCM is presently unavailable, further interrogation of the mechanisms behind loss of VEGFB function following diabetes is anticipated to help us advance the clinical management of DCM.

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Fatty acid (FA) provision to the heart is from cardiomyocyte and adipose depots, plus lipoprotein lipase (LPL) action. Changes in cardiac metabolism (reduced glucose, greater FA utilization) is a major contributor towards diabetic cardiomyopathy. Vascular endothelial growth factor B (VEGFB) can regulate coronary angiogenesis and influence energy metabolism. Multiple models of heart failure have indicated a significant drop in VEGFB. In this thesis we hypothesized that there is a role for VEGFB in diabetic cardiomyopathy. The objectives of this thesis were to: Determine the changes in cardiac metabolism following diabetes with its effect on VEGFB production. Investigate the mechanisms behind VEGFB action in the heart subsequent to diabetes. Identify the potential benefits of VEGFB following chronic diabetes. With increasing severity of diabetes and dramatic loss of insulin, the heart is unable to control its own FA supply using LPL and undergoes dramatic reprogramming that is linked to handling of excess FA that arise from adipose tissue. This transition results in a cardiac metabolic signature that exhibits mitochondrial FA overload, oxidative stress, triglyceride storage and cell death. Under these conditions VEGFB production is impaired. Mechanistically, the immediate response to high glucose and the secretion of endothelial heparanase is the release of cardiomyocyte surface bound VEGFB, which triggers signaling pathways and gene expression to influence cardiomyocyte (autocrine action) and endothelial cell (paracrine effects) survival. Defects in numerous VEGFB pathways were associated with an increased cell death signature in our models of diabetes. Overexpression of VEGFB in the heart can regulate coronary angiogenesis and influence energy metabolism and we tested whether these effects can overcome the detrimental consequences of diabetes. VEGFB overexpression induced an angiogenic response that resulted in greater delivery of insulin, amplifying its action in the TG (transgenic) heart. Additional mechanisms contributing towards enhancing insulin sensitivity included less delivery of lipoprotein lipase-derived FA, reduced accumulation of diacylglycerols and LysoPC and lower FA metabolism. The augmented effects on insulin action were preserved following diabetes. Our data suggest that using VEGFB as a cardio protective therapy against diabetic cardiomyopathy may be an intriguing and previously unappreciated approach.

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Enzymatically-active heparanase (HepA) has been implicated as an essential metabolic adaptation in the heart following diabetes. However, the regulation of the enzymatically-inactive heparanase (HepL) remain poorly understood. We hypothesized that in response to high glucose (HG) and secretion of HepL from the endothelial cell (EC), HepL uptake and function can protect the cardiomyocyte by modifying its cell death signature. HG promoted both HepL and HepA secretion from EC, with subsequent uptake of HepL into cardiomyocytes. This occurred through a low-density lipoprotein receptor-related protein 1 (LRP1) dependent mechanism, as LRP1 inhibition significantly reduced uptake. Exogenous addition of HepL to rat cardiomyocytes produced a dramatically altered expression of apoptosis-related genes, and protection against HG and H₂O₂ induced cell death. Cardiomyocytes from acutely diabetic rats demonstrated a robust increase in LRP1 expression and levels of heparanase, a pro-survival gene signature, and limited evidence of cell death, observations that were not apparent following chronic and progressive diabetes. We also tested if overexpression of heparanase can protect the heart against chemically induced or ischemia/reperfusion (I/R) injury. Mice overexpressing heparanase (Hep-tg) displayed physiological cardiac hypertrophy and changes in expression of genes related to the stress response, immune response, cell death, and development. These transcriptomic alterations were associated with promotion of unfolded protein response (UPR), autophagy, and oxidative stress resistance in a pro-survival direction. The UPR activation was adaptive and not apoptotic, and together with mTOR inhibition, induced autophagy. Subjecting wild type mice to thapsigargin evoked a transition from adaptive to apoptotic UPR, an effect attenuated in Hep-tg hearts. When exposed to I/R, infarct size and apoptosis were significantly lower in the Hep-tg heart, an effect reversed by inhibitors of UPR and autophagy. Our results highlight EC-to-cardiomyocyte transfer of heparanase to modulate the cardiomyocyte cell death signature. This mechanism was observed in the acutely diabetic heart, and its interruption following chronic diabetes may contribute towards the development of diabetic cardiomyopathy. Moreover, we established that the mechanisms by which heparanase promotes cell survival in cancer could be uniquely beneficial to the heart and exploited as a therapeutic target for the treatment of heart disease.

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In the diabetic heart, there is excessive dependence on fatty acid (FA) utilization to generate ATP. Lipoprotein lipase (LPL)-mediated hydrolysis of circulating triglyceride is suggested to be the predominant source of FA for cardiac utilization during diabetes. In the heart, LPL is produced in the cardiomyocytes and is transferred by its transporter glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) to the apical side of the endothelial cell (EC), where the enzyme is functional. We tested whether EC responds to hyperglycemia by increasing GPIHBP1. Streptozotocin diabetes increased cardiac LPL activity and GPIHBP1 gene and protein expression. Exposure of EC to high glucose-induced GPIHBP1 expression and amplified LPL shuttling across these cells. This effect coincided with an elevated secretion of heparanase, which can promote secretion of vascular endothelial growth factor (VEGF) from EC and cardiomyocytes. Recombinant VEGF induced EC GPIHBP1 mRNA and protein expression through activation of Notch signaling, which encompassed delta-like ligand 4 (DLL4) augmentation and nuclear translocation of the Notch intracellular domain. In addition, high glucose-induced secretion of heparanase is taken up by the cardiomyocyte to stimulate matrix-metalloproteinase (MMP) 9 expression and conversion of latent to active transforming growth factor-β (TGFβ). In the cardiomyocyte, TGFβ activation of RhoA enhances actin cytoskeleton rearrangement to promote LPL trafficking and secretion onto cell surface heparan sulfate proteoglycans. In the EC, TGFβ signaling promotes mesodermal homeobox 2 (Meox2) translocation to the nucleus that increases the expression of GPIHBP1, which facilitates movement of LPL to the vascular lumen. Collectively, EC, as the first responders to hyperglycemia, can release heparanase to liberate myocyte VEGF, which activates EC Notch signaling to facilitate GPIHBP1-mediated translocation of LPL across EC. Heparanase also induced MMP9 mediated activation of TGFβ. Its action on the cardiomyocyte to promote movement of LPL, together with its action on the EC to facilitate LPL shuttling are mechanisms that accelerate FA utilization by the diabetic heart. Gaining more insight into the mechanisms by which cardiac LPL is regulated may assist other researchers in devising new therapeutic strategies restore metabolic equilibrium, curb lipotoxicity, and help prevent or delay heart dysfunction characteristic of diabetes.

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Heparanase, a protein with enzymatic and non-enzymatic properties, contributes towards disease progression and prevention. We have reported that high glucose (HG) stimulates heparanase secretion from endothelial cells (EC) to cleave cardiomyocyte heparan sulfate and release bound lipoprotein lipase (LPL) for transfer to the vascular lumen. We examined whether heparanase also has a function to release cardiomyocyte vascular endothelial growth factor (VEGF), and whether this growth factor influences cardiomyocyte fatty acid (FA) delivery. HG promoted both latent and active heparanase secretion into EC conditioned medium, an effective stimulus for releasing cardiomyocyte VEGF. Intriguingly, latent heparanase was more efficient than active heparanase in releasing VEGF from a cell surface pool. VEGF augmented cardiomyocyte intracellular calcium, AMPK phosphorylation and heparin-releasable LPL. Our data suggest that the heparanase-LPL-VEGF axis amplifies FA delivery, an adaptive mechanism that is geared to overcome the loss of glucose consumption by the diabetic heart. If prolonged, the resultant lipotoxicity could lead to cardiovascular disease in humans. Therefore, we globally overexpressed heparanase and evaluated whether excessive heparanase would exacerbate the development of diabetic cardiomyopathy. The transgenic mice (hep-tg) showed normal life span and fertility, with improved glucose homeostasis. Heparanase overexpression was associated with enhanced GSIS and hyperglucagonemia, in addition to changes in islet composition and structure. Strikingly, the pancreatic islet transcriptome was greatly altered in hep-tg mice with over 2000 genes differentially expressed. The upregulated genes were enriched for diverse functions including cell death regulation, extracellular matrix component synthesis, and pancreatic hormone production. The downregulated genes were tightly linked to regulation of the cell cycle. In response to multiple low-dose STZ, hep-tg animals developed less severe hyperglycemia compared to WT, an effect likely related to their remaining beta cells that were more functionally efficient. In animals given a single high dose of STZ, causing severe hyperglycemia related to the catastrophic loss of insulin, hep-tg mice continued to have significantly lower blood glucose. In these mice, protective pathways were uncovered for managing hyperglycemia and include augmentation of FGF21 and GLP-1. Overall, this thesis uncovers opportunities to utilize both enzymatic and non-enzymatic properties of heparanase in managing diabetes and its complications.

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In diabetes, when glucose consumption is restricted, the heart adapts to use fatty acid (FA) exclusively. The majority of FA provided to the heart comes from breakdown of circulating triglyceride, a process catalyzed by lipoprotein lipase (LPL) located at the vascular lumen. Transfer of LPL from cardiomyocytes to the coronary lumen requires liberation of LPL from the myocyte surface heparan sulfate proteoglycans (HSPGs) with subsequent replenishment of this reservoir. We examined the contribution of coronary endothelial cells (EC) and cardiomyocytes towards regulation of LPL function following diabetes. To induce acute hyperglycemia, diazoxide (DZ), a selective ATP-sensitive K+ channel opener was used. For chronic diabetes, streptozotocin (STZ), a β-cell specific toxin was administered at doses of 55 (D55) or 100 (D100) mg/kg to generate moderate and severe diabetes, respectively. Cardiac LPL processing into active dimers and breakdown at the vascular lumen was investigated. Following acute hyperglycemia and moderate diabetes, more LPL is processed into an active dimeric form, which involves the endoplasmic reticulum chaperone calnexin in cardiomyocytes. Severe diabetes results in increased conversion of LPL into inactive monomers at the vascular lumen, a process mediated by FA-induced expression of angiopoietin-like protein 4. On exposure of bovine coronary artery EC to high glucose, both latent and active heparanase were released into the medium, termed ECCM. ECCM liberated LPL from the myocyte surface, in addition to facilitating its replenishment. Of the two forms of heparanase secreted from EC in response to high glucose, active heparanase released LPL from the myocyte surface, whereas latent heparanase stimulated reloading of LPL from an intracellular pool via HSPG-mediated RhoA activation. Latent heparanase can be also taken up by cardiomyocytes, converted into active heparanase in lysosomes, and its nuclear entry likely to modulate gene expression. Results from this study advance our understanding of how the cross-talk between EC and cardiomyocytes facilitate LPL secretion and how diabetes influences coronary LPL maturation and turnover. Pharmaceutical manipulation of these pathways could potentially provide an additional strategy to limit FA delivery to the heart, and prevent cardiomyopathy seen with chronic diabetes.

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Glucocorticoids increase PDK4 mRNA and protein expression, which phosphorylates PDH, thereby preventing the formed pyruvate from undergoing mitochondrial oxidation. This increase in PDK4 expression is mediated by the mandatory presence of FoxOs in the nucleus. Rat cardiomyocytes exposed to Dx produced a robust decrease in glucose oxidation. Measurement of FoxO compartmentalization demonstrated increase in nuclear, but resultant decrease in cytosolic content of FoxO1 with no change in the total content. The increase in nuclear content of FoxO1 correlated to an increase in nuclear phospho p38 MAPK together with a robust association between this transcription factor and kinase. Dx also promoted nuclear retention of FoxO1 through a decrease in phosphorylation of Akt, an effect mediated by heat shock proteins binding to Akt. Instead, Dx increased the association of Sirt1 with FoxO1, thereby causing a decrease in FoxO acetylation. Our data suggests that FoxO1 has a major PDK4 regulating function. Related to nutrient excess, FoxO1 has a role in regulating fatty acid (FA) uptake and oxidation, and triglyceride storage by mechanisms that are largely unresolved. We examined the mechanism behind palmitate (PA) induced TG accumulation in cardiomyocytes. PA treated cardiomyocytes showed substantial increase in TG accumulation, accompanied by amplification in nuclear migration of phospho-p38 and FoxO1, iNOS induction and translocation of CD36 to the plasma membrane. PA also increased Cdc42 protein and its tyrosine nitration, there by re-arranging the cytoskeleton and facilitating CD36 translocation. Cardiomyocyte cell death is a major contributing factor for diabetic cardiomyopathy, and multiple mechanisms have been proposed for its initiation. Diabetes increased the nuclear content of FoxO1 as a result of attenuated survival signalling. Increased nuclear FoxO1 augmented iNOS induction in the diabetic myocardium. The iNOS induced nitrosative stress increased the nitrosylation of GAPDH accompanied by its binding to Siah1 and translocation to the nucleus with an increased nuclear nitrosative stress. iNOS also nitrosylated caspase-3 there by hindering its ability to cleave PARP, a direct downstream target of Caspase-3. The resultant effect is activation of PARP with an nuclear compartmentalization of Apoptosis Inducing Factor (AIF) and resultant cell death.

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Following diabetes, the heart increases its lipoprotein lipase (LPL) at the coronary lumen by transferring LPL from the cardiomyocyte to the endothelial lumen. Heparanase is an endoglycosidase that specifically cleaves carbohydrate chains of heparan sulfate (HS). We examined the mechanisms behind endothelial heparanase control of cardiac LPL translocation. Using diazoxide (DZ) to decrease serum insulin, we observed that within 30 min of DZ, interstitial heparanase increased, an effect that closely mirrored an augmentation in interstitial LPL. In bovine coronary artery endothelial cells incubated with glucose or palmitic acid (PA), glucose dose-dependently increased heparanase secretion, a process that required ATP release, purinergic receptor activation, cortical actin disassembly and stress actin formation. Phosphorylation of filamin likely contributed towards the cortical actin disassembly, whereas Ca²⁺/calmodulin-dependent protein kinase II and p38 mitogen activated protein kinase/heat shock protein 25 phosphorylation mediated stress actin formation. The endothelial-secreted heparanase in response to HG demonstrated endoglycosidase activity, cleaved HS, and released attached proteins like lipoprotein lipase and basic fibroblast growth factor. Unlike glucose, PA increased intracellular heparanase and induced rapid nuclear accumulation of heparanase that was dependent on Bax activation and lysosome permeabilization. Heat shock protein 90 was an important mediator of PA-induced shuttling of heparanase to the nucleus. Nuclear heparanase promoted cleavage of HS, a potent inhibitor of histone acetyltransferase activity and gene transcription. A TaqMan gene expression assay revealed an increase in genes related to glucose metabolism and inflammation. In addition, glycolysis was uncoupled from glucose oxidation, resulting in accumulation of lactate. Our data suggest that following hyperglycemia, translocation of LPL from the cardiomyocyte cell surface to the apical side of endothelial cells is influenced by the ability of fatty acid to increase endothelial intracellular heparanase followed by rapid secretion of this enzyme by glucose. Given that both LPL and heparanase have been implicated in the progression of diabetes, our data may serve to reduce the associated cardiovascular complications by limiting the utilization of fatty acid after diabetes.

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During diabetes, when cardiac glucose utilization is impaired, the heart switches to exclusivelyusing fatty acid (FA) for energy supply. This metabolic switching could lead to cardiomyocytecell death, and eventually to heart disease. One mechanism for providing the heart with FA islipoprotein lipase (LPL). LPL, synthesized in cardiomyocytes, is transferred to the vascularlumen where it catalyzes the breakdown of lipoprotein-triglyceride (TG) to provide FA to theheart. Following diabetes, heparin-releasable LPL activity at the coronary lumen increases bymechanisms that have yet to completely elucidated. Using diazoxide (DZ), an agent thatdecreases insulin secretion and causes hyperglycemia, we induced a substantial increase in LPLactivity at the vascular lumen. In these hyperglycemic animals, we demonstrate thatphosphorylation of AMPK, p38 MAPK, and heat shock protein (Hsp)25 produced actincytoskeleton rearrangement. This structural rearrangement facilitated LPL translocation to themyocyte cell surface and eventually, the vascular lumen. Parallel to this mechanism, the robustphosphorylation of Hsp25 allowed PKCdelta to activate protein kinase D (PKD), an importantkinase that regulates fission of vesicles from Golgi membranes. Rottlerin, a PKCdelta inhibitor,prevented PKD phosphorylation and the subsequent increase in coronary LPL. In myocytes inwhich PKD was silenced or a mutant form of PKCdelta was expressed, these cells were incapable ofincreasing LPL. Results from these studies could help in restricting cardiac LPL translocation,lowering FA delivery to the heart, and strategies to overcome contractile dysfunction followingdiabetes. We also evaluated the process which restricts LPL at the vascular lumen, especiallyduring severe diabetes with its associated increase in hepatic lipoprotein TG secretion andadipose tissue lipolysis. Following severe hypoinsulinemia and hyperlipidemia induced bystreptozotocin, we reported that activation of caspase-3, together with loss of 14-3-3zeta, restricted LPL translocation to the vascular lumen. When caspase-3 was inhibited, this compensatoryresponse was lost, leading to profound lipid accumulation in the heart through promotion of LPLactivity. Thus, although caspase-3 inhibition has been suggested to attenuate cardiacdysfunction, its inhibition following severe diabetes may induce cardiac damage through strikingTG accumulation in the heart.

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Insulin resistance (IR) and elevated blood pressure (BP) are two key features of the metabolic syndrome, which play an important role in the development of secondary cardiovascular complications. Feeding rats a diet rich in sugars such as fructose induces IR followed by vascular abnormalities and elevation in BP. Insulin resistance impairs the fine balance between endothelial vasoconstrictors and vasorelaxants, which results in endothelial dysfunction (ED). Differences in sex hormones play an important role in the development of insulin resistance and blood pressure as testosterone is essential for the development of ED and the increase in BP. Testosterone regulates the cyclooxygenase and Cyp4A-catalyzed metabolites of arachidonic acid, which have been implicated in vascular homeostasis. However, their regulation by insulin is unclear. We hypothesized that In the presence of testosterone insulin resistance favors increased synthesis of vasoconstrictor metabolites of arachidonic acid, which contributes to the development of endothelial dysfunction and subsequent elevation of blood pressure. Intact and/or gonadectomized male Wistar rats were fed for 9-12 weeks with fructose following which changes in blood pressures and vascular reactivity were determined. Treatment with testosterone restored the elevated blood pressure in gonadectomized rats. In addition, fructose-feeding induced insulin resistance in intact rats, which was ameliorated by inhibiting the androgen receptor or 20-HETE synthesis. Insulin resistance increased Cyp4A1, 2/3 expression in the superior mesenteric artery (SMA), which was decreased by blocking testosterone function. Finally, the increase in BP and Cyp4A1, 2/3 were prevented by treating rats for 2 weeks with the Cyp4A inhibitor HET0016. The role of IR in arachidonate metabolism was evaluated by treatment with metformin (500 mg/kg) for 10 weeks. Prevention of insulin resistance prevented both endothelial dysfunction and the increase in BP. Further, inhibition of Cyp4A by DDMS improved endothelial relaxation in the SMA of only intact and untreated FFR but not the gonadectomized and metformin-treated groups. Similar effects were observed upon blocking COX with indomethacin. IR increased the participation of COX-2, which was testosterone-dependent in both aorta and SMA. In conclusion, in the presence of testosterone, IR induces vascular complications by altering arachidonic acid metabolism to increase vasoconstrictor levels.

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Following hypoinsulinemia, glucose utilization is compromised and the myocardium switches to utilize fatty acids (FA). Previous studies have reported that PPAR-α promotes FA oxidation during chronic hypoinsulinemia. Whether the same modification also occurs in the heart during acute hypoinsulinemia and if AMP-activated protein kinase (AMPK) participates in the increase of cardiac fatty acid oxidation during this condition remains unclear. Using streptozotocin model of Type I diabetes, we report that in acute (4 days) diabetes AMPK by phosphorylating acetyl CoA carboxylase promotes cardiac fatty acid oxidation. Unexpectedly, in chronic diabetes (6 weeks), with the addition of augmented plasma and heart lipids, AMPK activation is prevented, and PPAR-α through its regulation of downstream targets controls myocardial FA oxidation. In addition to its role in FA utilization, AMPK has been implicated in controlling FA delivery through its regulation of the FA transporter, CD36. Given that LPL derived FA is the principal source of energy during insulin resistance, the question of interest was whether cardiac AMPK can regulate LPL translocation to the vascular lumen to increase the exogenous FA pool. Using dexamethasone (DEX) as an acute model of insulin resistance, my study demonstrates that, following a single dose of DEX, nongenomic phosphorylation of stress kinases such as AMPK together with insulin facilitate LPL translocation to the myocyte cell surface. Besides metabolism, AMPK has been implicated in modulating cell death. The production of tumor necrosis factor alpha (TNF-α) is reported to increase during obesity and diabetes and elevated plasma or endogenous cardiac TNF-α levels have shown to cause cardiomyocyte apoptosis. Using established AMPK activators like DEX or metformin (MET), my objective was to determine if AMPK activation prevents TNF-α-induced apoptosis in cardiomyocytes. My data demonstrates that although DEX and MET are used as anti-inflammatory agents or insulin sensitizers, their common property to phosphorylate AMPK promotes cardiomyocyte survival through its regulation of Bad and the mitochondrial apoptotic mechanism.

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Lysophosphatidylcholine (1-acyl-sn-glycero-3-phosphocholine, LPC) is the most abundant glycerol-based lysophospholipid present in cell membranes and oxidized lipoproteins. It has been proposed that LPC contributes to the altered vaso-reactivity associated with various cardiovascular diseases in which elevated LPC levels were identified. However, the contribution of LPC in regulating vascular resistance has not been completely elucidated, as the majority of previous studies have used either large blood vessels or isolated cells. Therefore, our study aimed to investigate the vasoactive effects and the underlying mechanisms of LPC in small arteries/arterioles that are crucial in the determination of vascular resistance and the maintenance of organ function.The unique finding of our investigation is that LPC possesses biphasic effects on both peripheral arterial resistance and coronary circulation, and even ventricular function. Specifically, in the isolated perfused rat mesenteric arterial bed, both endothelium-derived relaxing factors and thromboxane A₂ (TxA₂, a vasoconstricor) are diminished by LPC perfusion. However, LPC washout stimulates a rebound overproduction of TxA₂, which results in an enhanced contractile response to alpha1-adrenoceptor stimulation.Our study next found that sustained perfusion of hearts with LPC augmented coronary perfusion pressure and reduced left ventricular developed pressure. These effects were exaggerated when LPC was removed from the perfusate. Furthermore, LPC selectively potentiated the receptor-coupled vasoconstrictor response of isolated rat septal coronary artery to U-46619, a TxA₂ mimetic. Interestingly, when LPC was washed out, the potentiation to U-46619 was even more pronounced. Both the immediate and residual effects of LPC were endothelium-dependent. Endothelium-derived hyperpolarizing factor was likely the sole mediator responsible for the direct effects of LPC on U-46619-vasoconstriction, whereas the augmented vasoconstrictor responses following LPC washout may in part be related to an increase in endothelin-1, and a striking reduction in the bioavailability of nitric oxide.Our data suggest that simply reducing LPC levels to normal may not be sufficient to reverse the adverse consequences of this lysolipid accumulation in vasculature. Further understanding of the residual effects of LPC will enable the identification of more effective treatment targets for LPC-related diseases.

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