Objective: Current antiplatelet medications increase the risk of bleeding, which leads to a clear clinical need in developing novel mechanism-based antiplatelet drugs. TYMP (Thymidine phosphorylase), a cytoplasm protein that is highly expressed in platelets, facilitates multiple agonist-induced platelet activation, and enhances thrombosis. Tipiracil hydrochloride (TPI), a selective TYMP inhibitor, has been approved by the Food and Drug Administration for clinical use. We tested the hypothesis that TPI is a safe antithrombotic medication. Approach and Results: By coexpression of TYMP and Lyn, GST (glutathione S-transferase) tagged Lyn-SH3 domain or Lyn-SH2 domain, we showed the direct evidence that TYMP binds to Lyn through both SH3 and SH2 domains, and TPI diminished the binding. TYMP deficiency significantly inhibits thrombosis in vivo in both sexes. Pretreatment of platelets with TPI rapidly inhibited collagen- and ADP-induced platelet aggregation. Under either normal or hyperlipidemic conditions, treating wild-type mice with TPI via intraperitoneal injection, intravenous injection, or gavage feeding dramatically inhibited thrombosis without inducing significant bleeding. Even at high doses, TPI has a lower bleeding side effect compared with aspirin and clopidogrel. Intravenous delivery of TPI alone or combined with tissue plasminogen activator dramatically inhibited thrombosis. Dual administration of a very low dose of aspirin and TPI, which had no antithrombotic effects when used alone, significantly inhibited thrombosis without disturbing hemostasis. Conclusions: This study demonstrated that inhibition of TYMP, a cytoplasmic protein, attenuated multiple signaling pathways that mediate platelet activation, aggregation, and thrombosis. TPI can be used as a novel antithrombotic medication without the increase in risk of bleeding.
Objective— Dysregulated proliferation of vascular smooth muscle cells (VSMC) plays an essential role in neointimal hyperplasia. CD36 functions critically in atherogenesis and thrombosis. We hypothesize that CD36 regulates VSMC proliferation and contributes to the development of obstructive vascular diseases. Approach and Results— We found by immunofluorescent staining that CD36 was highly expressed in human vessels with obstructive diseases. Using guidewire-induced carotid artery injury and shear stress–induced intima thickening models, we compared neointimal hyperplasia in Apoe −/− , Cd36 −/− /Apoe −/− , and CD36 specifically deleted in VSMC (VSMC cd36 −/− ) mice. CD36 deficiency, either global or VSMC-specific, dramatically reduced injury-induced neointimal thickening. Correspondingly, carotid artery blood flow was significantly increased in Cd36 −/− /Apoe −/− compared with Apoe −/− mice. In cultured VSMCs from thoracic aorta of wild-type and Cd36 −/− mice, we found that loss of CD36 significantly decreased serum-stimulated proliferation and increased cell populations in S phase, suggesting that CD36 is necessary for VSMC S/G2-M-phase transition. Treatment of VSMCs with a TSR (thrombospondin type 1 repeat) peptide significantly increased wild-type, but not Cd36 −/− VSMC proliferation. TSR or serum treatment significantly increased cyclin A expression in wild-type, but not in Cd36 −/− VSMCs. STAT3 (signal transducer and activator of transcription), which reportedly enhances both VSMC differentiation and maturation, was higher in Cd36 −/− VSMCs. CD36 deficiency significantly decreased expression of Col1A1 (type 1 collagen A1 chain) and TGF-β1 (transforming growth factor beta 1), and increased expression of contractile proteins, including calponin 1 and smooth muscle α actin, and dramatically increased cell contraction. Conclusions— CD36 promotes VSMC proliferation via upregulation of cyclin A expression that contributes to the development of neointimal hyperplasia, collagen deposition, and obstructive vascular diseases.
Methamphetamine use during pregnancy can have negative consequences on the offspring. However, most studies investigating the impact of prenatal exposure to methamphetamine have focused on behavioral and neurological outcomes. Relatively little is known regarding the impact of prenatal methamphetamine on the adult cardiovascular system. This study investigated the impact of chronic fetal exposure to methamphetamine on vascular function in adult offspring. Pregnant female rats received daily saline or methamphetamine (5 mg/kg) injections starting on gestational day 1 and continuing until the pups were born. Vascular function was assessed in 5 month old offspring. Prenatal methamphetamine significantly decreased both the efficacy and potency of acetylcholine-induced relaxation in isolated male (but not female) aortas when perivascular adipose tissue (PVAT) remained intact. However, prenatal methamphetamine had no impact on acetylcholine-induced relaxation when PVAT was removed. Nitroprusside-induced relaxation of the aorta was unaffected by prenatal methamphetamine. Angiotensin II-induced contractile responses were significantly potentiated in male (but not female) aortas regardless of the presence of PVAT. This effect was reversed by L-nitro arginine methyl ester (L-NAME). Serotonin- and phenylephrine-induced contraction were unaffected by prenatal methamphetamine. Prenatal methamphetamine had no impact on acetylcholine-induced relaxation of third order mesenteric arteries and no effect on basal blood pressure. These data provide evidence that prenatal exposure to methamphetamine sex-dependently alters vasomotor function in the vasculature and may increase the risk of developing vascular disorders later in adult life.
Methamphetamine is one of the most commonly used illicit drugs during pregnancy. Most studies investigating the impact of maternal use of methamphetamine on children have focused on neurological outcomes. In contrast cardiovascular outcomes in these children have not been characterized. Recent studies in rodents provide evidence that prenatal exposure to methamphetamine induces changes in cardiac gene expression, changes in the heart’s susceptibility to ischemic injury, and changes in vascular function that may increase the risk of developing cardiovascular disorders later in life. Importantly, these changes are sex-dependent. This review summarizes our current understanding of how methamphetamine use during pregnancy impacts the cardiovascular function of adult offspring and highlight gaps in our knowledge of the potential cardiovascular risks associated with prenatal exposure to methamphetamine.
Obesity is a major independent risk factor for the development of type II diabetes (T2DM), nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD). Consequently, controlling obesity constitutes a key strategy for reducing the prevalence of these diseases. The majority of drugs developed for treating obesity over the past 20 years have been withdrawn due to the increased risk of cardiovascular and psychiatric complications. Therefore, developing novel mechanism-mediated therapeutics for controlling obesity and its consequent complications is a top priority and urgently needed. Our studies indicate that thymidine phosphorylase (TYMP) could be a promising target. The traditional role of TYMP is to catalyze the reversible conversion of thymidine to thymine and 2-deoxy-D-ribose-1 phosphate and maintain the homeostatic nuclear pool of these molecules. TYMP expression is increased in several diseased conditions, including obesity, T2DM, and NAFLD. However, whether TYMP plays a role in the development of these diseases is unknown. We found that Tymp-deficient (Tymp-/-) male mice exhibited significantly limited body weight gain as well as liver and perigonadal fat weight when fed either a western diet (TD.88137) or a prodiabetic high-fat diet (D12492) compared with the wild-type mice. Male Tymp-/- mice showed better glucose tolerance. TYMP-deficiency reduced expression of enzymes that confer glycolysis and de novo lipogenesis in the liver. TYMP-deficiency enhanced the sensitivity of primary hepatocytes to insulin as evidenced by the increase of AKT activation. Inhibition of TYMP with tipiracil, a selective, potent, and the FDA approved TYMP inhibitor, dramatically reduced western diet and high-fat diet-induced body weight gain. We conclude that TYMP plays a pivotal role in liver glucose and lipid metabolism, which promotes the development of obesity and T2DM. Targeting TYMP with tipiracil could be a new therapy for obesity. Disclosure H. Yue: None. A. M. Belcher: None. A. Bicak: None. W. Li: None.
We sought to assess the impact of transcatheter aortic valve replacement (TAVR) on patients that have both severe aortic stenosis (SAS) and liver cirrhosis on mortality at 365 days after index event. We identified 19,210 patients that met inclusion criteria using the TriNetX database consisting of data from 58 large healthcare organizations collected between January 1, 2010 and February 24, 2022. Of those patients, 1,283 (3.2%) had SAS with liver cirrhosis that had a TAVR, and 19,210 (96.8%) had SAS with liver cirrhosis that did not have a TAVR. We analyzed the data to compare all-cause mortality at 365 days utilizing the TriNetX web platform. Additionally, we conducted propensity score matching (PSM) to reduce the effects of confounders between the two groups. Patients with SAS and liver cirrhosis that had a TAVR were older (72.4±9.7 vs 68.0±11.8, P<0.001), and they had higher rates of heart failure (71.2% vs 34.5%, P<0.001), coronary artery disease (72.0% vs 31.2%, P<0.001), diabetes (52.5% vs 41.2%, P<0.001), and chronic kidney disease (43.8% vs 30.1%, P<0.001) compared to patients with SAS and liver cirrhosis without TAVR. PSM created two well-matched cohorts of 1,269 patients each. The TAVR group had a lower mortality rate compared to the no TAVR group (22.5% vs 34.8%, P<0.0001) at 365 days. This was confirmed using a log-rank test. Given these data, it appears that there is a mortality benefit associated with TAVR in patients with SAS and liver cirrhosis.
Background Prenatal exposure to central nervous system stimulants such as cocaine, nicotine, and caffeine alters cardiovascular function in adult offspring. Methamphetamine use during pregnancy is associated with negative consequences in the offspring. However, most studies of methamphetamine use during pregnancy have focused on behavioral and neurological outcomes. Relatively little is known regarding the impact of prenatal methamphetamine exposure on the adult cardiovascular system. This study examined the hypothesis that methamphetamine use during pregnancy alters contractile function of the vasculature in the adult offspring. We also investigated the role of perivascular adipose tissue (PVAT) in methamphetamine‐induced changes in vascular function. Methods Pregnant female rats received daily injections of saline or methamphetamine (5 mg/kg) throughout gestation. Agonist‐induced contraction and relaxation responses were measured in aortas of 5 month old offspring in the presence and absence of perivascular adipose tissue. Results Prenatal methamphetamine significantly attenuated acetylcholine‐induced relaxation in male (but not female) aortas when PVAT remained intact. However, prenatal methamphetamine had no impact on acetylcholine‐induced relaxation when PVAT was removed. Nitroprusside‐induced relaxation was unaffected by prenatal methamphetamine. Prenatal exposure to methamphetamine had no impact on acetylcholine‐induced relaxation in third order mesenteric arteries of male or female offspring regardless of the presence of PVAT. Angiotensin II‐induced contractile responses were significantly potentiated in male (but not female) aortas regardless of the presence of PVAT. This effect was abolished by L‐Nitro arginine methyl ester (L‐NAME). Contractile responses to phenylephrine and serotonin were unaffected in both male and female aortas. Basal blood pressure in adult male and female offspring was also unaffected by prenatal exposure to methamphetamine. Conclusions Prenatal exposure to methamphetamine sex‐dependently alters PVAT function in the aorta. Methamphetamine also enhances angiotensin II‐induced contraction through a mechanism that involves suppression of nitric oxide signaling. These data provide evidence that methamphetamine use during pregnancy induces sex‐dependent changes in the vasculature that may increase the risk of cardiovascular disease in adult offspring.
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