Oleic acid induces smooth muscle foam cell formation and enhances atherosclerotic lesion development via CD36

<p>Abstract</p> <p>Background</p> <p>Elevated plasma free fatty acid (FFA) levels have been linked to the development of atherosclerosis. However, how FFA causes atherosclerosis has not been determined. Because fatty acid translocase (FAT/CD36) is responsible for the uptake of FFA, we hypothesized that the atherogenic effects of FFA may be mediated via CD36.</p> <p>Results</p> <p>We tested this hypothesis using cultured rat aortic smooth muscle cells (SMCs) treated with oleic acid (OA). We found that OA induces lipid accumulation in SMCs in a dose dependent manner. Rat aortic SMCs treated for 48 hours with OA (250 μmol/L) became foam cells based on morphological (Oil Red O staining) and biochemical (5 times increase in cellular triglyceride) criteria. Moreover, specific inhibition of CD36 by sulfo-N-succinimidyl oleate significantly attenuated OA induced lipid accumulation and foam cell formation. To confirm these results <it>in vivo</it>, we used ApoE-deficient mice fed with normal chow (NC), OA diet, NC plus lipolysis inhibitor acipimox or OA plus acipimox. OA-fed mice showed increased plasma FFA levels and enhanced atherosclerotic lesions in the aortic sinus compared to the NC group (both <it>p </it>< 0.01). This effect was partially reversed by acipimox (lesion area: OA: 3.09 ± 0.10 ×10⁵μm²vs. OA plus acipimox: 2.60 ± 0.10 ×10⁵μm², <it>p </it>< 0.05; FFA: OA: 0.91 ± 0.03 mmol/L vs. OA plus acipimox: 0.78 ± 0.03 mmol/L, <it>p </it>< 0.05).</p> <p>Conclusions</p> <p>These findings suggest that OA induces smooth muscle foam cell formation and enhances atherosclerotic lesions in part though CD36. Furthermore, these findings provide a novel model for the investigation of atherosclerosis.</p

TRPV1 protects renal ischemia-reperfusion injury in diet-induced obese mice by enhancing CGRP release and increasing renal blood flow

Background Obesity is a major risk factor for end-stage renal disease. Using transient receptor potential vanilloid 1 knockout (TRPV1−/−) mice, we tested the hypothesis that TRPV1 protects against obesity-induced exacerbation of renal ischemia-reperfusion (I/R) injury. Methods TRPV1−/− and wild-type (WT) mice were fed a chow or Western diet (WD) for 22–23 weeks. After that, mice were subjected to renal I/R injury, and renal cortical blood flow (CBF) and medullary blood flow (MBF) were measured. Results The Western diet significantly increased body weight and fasting blood glucose levels in both TRPV1−/− and WT mice. WD-induced impairment of glucose tolerance was worsened in TRPV1−/− mice compared with WT mice. WD intake prolonged the time required to reach peak reperfusion in the cortex and medulla (both P < 0.05), decreased the recovery rate of CBF (P < 0.05) and MBF (P < 0.05), and increased blood urea nitrogen, plasma creatinine, and urinary 8-isoprostane levels after I/R in both mouse strains, with greater effects in TRPV1−/− mice (all P < 0.05). Renal I/R increased calcitonin gene-related peptide (CGRP) release in WT but not in TRPV1−/− mice, and WD attenuated CGRP release in WT mice. Moreover, blockade of CGRP receptors impaired renal regional blood flow and renal function in renal I/R injured WT mice. Conclusion These results indicate that TRPV1 plays a protective role in WD-induced exacerbation of renal I/R injury probably through enhancing CGRP release and increasing renal blood flow

Activation of TRPV1 Prevents Salt-Induced Kidney Damage and Hypertension After Renal Ischemia-Reperfusion Injury in Rats

Background/Aims: High-salt intake after recovery from renal ischemia-reperfusion (I/R) injury leads to hypertension with severe renal damage. Transient receptor potential vanilloid type 1 (TRPV1) channels have been involved in the regulation of inflammation and oxidative stress following ischemic organ injury. We tested the hypothesis that activation of TRPV1 conveys preconditioning protection to the kidney subjected to I/R. Methods: TRPV1 was activated or down-regulated by subcutaneous injection of a low (1mg/kg) or high (100mg/kg) dose of capsaicin, respectively, 3 hours before ischemia. Rats were fed a 0.4% NaCl diet for 5 weeks after I/R followed by a 4% NaCl diet for 4 more weeks in 4 groups: sham, I/R, I/R+high-dose capsaicin (HCap), and I/R+low-dose capsaicin (LCap). Results: Renal TRPV1 expression was decreased in I/R rats (P&#x3c; 0.05) and further reduced in I/R+HCap group (P&#x3c; 0.05) but unchanged in I/R+LCap rats compared with the sham group. Blood pressure were elevated in I/R rats (P&#x3c; 0.05) and further increased in I/R+HCap group (P&#x3c; 0.05) but unchanged in I/R+LCap rats compared with sham. Renal function was impaired in I/R rats (P&#x3c; 0.05) and further deteriorated in I/R+HCap group (P&#x3c; 0.05) but unchanged in I/R+LCap group. Renal inflammatory responses, oxidative stress, and renal collagen deposition were augmented in I/R rats (all P&#x3c; 0.05) and further intensified in I/R+HCap group (all P&#x3c; 0.05) but unchanged in I/R+LCap group. Conclusion: Activation of TRPV1 plays an anti-inflammatory and anti-oxidative stress role in preventing renal tissue damage and salt-induced hypertension after I/R injury, indicating that TRPV1 conveys preconditioning protection that may have therapeutic implication

Uncoupling Protein 2 in Cardiovascular Health and Disease

Uncoupling protein 2 (UCP2) belongs to the family of mitochondrial anion carrier proteins. It uncouples oxygen consumption from ATP synthesis. UCP2 is ubiquitously expressed in most cell types to reduce oxidative stress. It is tightly regulated at the transcriptional, translational, and post-translational levels. UCP2 in the cardiovascular system is being increasingly recognized as an important molecule to defend against various stress signals such as oxidative stress in the pathology of vascular dysfunction, atherosclerosis, hypertension, and cardiac injuries. UCP2 protects against cellular dysfunction through reducing mitochondrial oxidative stress and modulation of mitochondrial function. In view of the different functions of UCP2 in various cell types that contribute to whole body homeostasis, cell type-specific modification of UCP2 expression may offer a better approach to help understanding how UCP2 governs mitochondrial function, reactive oxygen species production and transmembrane proton leak and how dysfunction of UCP2 participates in the development of cardiovascular diseases. This review article provided an update on the physiological regulation of UCP2 in the cardiovascular system, and also discussed the involvement of UCP2 deficiency and associated oxidative stress in the pathogenesis of several common cardiovascular diseases. Drugs targeting UCP2 expression and activity might serve another effective strategy to ameliorate cardiovascular dysfunction. However, more detailed mechanistic study will be needed to dissect the role of UCP2, the regulation of UCP2 expression, and the cellular responses to the changes of UCP2 expression in normal and stressed situations at different stages of cardiovascular diseases

Predictors and Management of Antiplatelet-Related Bleeding Complications for Acute Coronary Syndrome in Chinese Elderly Patients

Background/Aims: Bleeding complications after percutaneous coronary intervention (PCI) are strongly associated with adverse patient outcomes. However, there are no specific guidelines for the predictors and management of antiplatelet-related bleeding complications in Chinese elderly patients with acute coronary syndrome (ACS). Methods: A retrospective analysis of 237 consecutive patients (aged ≥ 75 years) with ACS who had undergone successful PCI from January 2010 to December 2016 was performed to identify predictors and management of antiplatelet-related bleeding complications. Multivariate logistic regression analysis was conducted to investigate independent predictors of antiplatelet-related bleeding complications. We defined antiplatelet-related bleeding complications as first hospitalization received long-term oral antiplatelet therapy and required hospitalization, including gastrointestinal and intracranial bleedings. Results: After multivariable adjustment, independent risk predictors of antiplatelet-related bleeding complications included female gender (odds ratio [OR]: 2.96; 95% confidence interval [CI]: 1.98 to 4.15; P = 0.011), body mass index (OR: 1.54; 95% CI: 1.06 to 1.94; P = 0.034), previous history of bleeding (OR: 4.03; 95% CI: 1.84 to 6.12; P = 0.004), fasting blood glucose (OR: 2.79; 95% CI: 1.23 to 4.46; P = 0.025), and chronic total occlusion lesion (OR: 4.69; 95% CI: 2.19 to 7.93; P = 0.007). Of 46 patients with antiplatelet-related bleeding complications, 54.3% were treated short-term dual antiplatelet therapy (DAPT) cessation (0–7 days) and 45.7% underwent long-term DAPT cessation (&#x3e; 7 days). Among these, 14 patients presented major adverse cardiac and cerebrovascular events (MACCE), whereas no re-bleeding happened over all available follow-up. The incidence of MACCE was not significantly different between the two groups one year after PCI (36.0% for short-term DAPT cessation versus 23.8% for long-term DAPT cessation, P = 0.522). Conclusion: For elderly patients with ACS, multiple factors were likely to contribute to antiplatelet-related bleeding complications, especially previous history of bleeding and chronic total occlusion lesion. Better individualized, tailored and risk-adjusted antiplatelet therapy after PCI is urgently needed in this high-risk population

Activation of TRPV1 by Dietary Capsaicin Improves Endothelium-Dependent Vasorelaxation and Prevents Hypertension

Some plant-based diets lower the cardiometabolic risks and prevalence of hypertension. New evidence implies a role for the transient receptor potential vanilloid 1 (TRPV1) cation channel in the pathogenesis of cardiometabolic diseases. Little is known about impact of chronic TRPV1 activation on the regulation of vascular function and blood pressure. Here we report that chronic TRPV1 activation by dietary capsaicin increases the phosphorylation of protein kinase A (PKA) and eNOS and thus production of nitric oxide (NO) in endothelial cells, which is calcium dependent. TRPV1 activation by capsaicin enhances endothelium-dependent relaxation in wild-type mice, an effect absent in TRPV1-deficient mice. Long-term stimulation of TRPV1 can activate PKA, which contributes to increased eNOS phosphorylation, improves vasorelaxation, and lowers blood pressure in genetically hypertensive rats. We conclude that TRPV1 activation by dietary capsaicin improves endothelial function. TRPV1-mediated increase in NO production may represent a promising target for therapeutic intervention of hypertension

Transient Receptor Potential Channels in Cardiovascular and Renal Diseases

Transient receptor potential (TRP) channels belong to a superfamily of integral membrane proteins with diverse functions in sensory perception and cellular physiology [...