The cardiac microvascular system, which is primarily composed of monolayer endothelial cells, is the site of blood supply and nutrient exchange to cardiomyocytes. However, microvascular ischemia/reperfusion injury (IRI) following percutaneous coronary intervention is a woefully neglected topic, and few strategies are available to reverse such pathologies. Here, we studied the effects of melatonin on microcirculation IRI and elucidated the underlying mechanism. Melatonin markedly reduced infarcted area, improved cardiac function, restored blood flow, and lower microcirculation perfusion defects. Histological analysis showed that cardiac microcirculation endothelial cells (CMEC) in melatonin‐treated mice had an unbroken endothelial barrier, increased endothelial nitric oxide synthase expression, unobstructed lumen, reduced inflammatory cell infiltration, and less endothelial damage. In contrast, AMP‐activated protein kinase α (AMPKα) deficiency abolished the beneficial effects of melatonin on microvasculature. In vitro, IRI activated dynamin‐related protein 1 (Drp1)‐dependent mitochondrial fission, which subsequently induced voltage‐dependent anion channel 1 (VDAC1) oligomerization, hexokinase 2 (HK2) liberation, mitochondrial permeability transition pore (mPTP) opening, PINK1/Parkin upregulation, and ultimately mitophagy‐mediated CMEC death. However, melatonin strengthened CMEC survival via activation of AMPKα, followed by p‐Drp1S616 downregulation and p‐Drp1S37 upregulation, which blunted Drp1‐dependent mitochondrial fission. Suppression of mitochondrial fission by melatonin recovered VDAC1‐HK2 interaction that prevented mPTP opening and PINK1/Parkin activation, eventually blocking mitophagy‐mediated cellular death. In summary, this study confirmed that melatonin protects cardiac microvasculature against IRI. The underlying mechanism may be attributed to the inhibitory effects of melatonin on mitochondrial fission‐VDAC1‐HK2‐mPTP‐mitophagy axis via activation of AMPKα.

This study provides Class II evidence that in patients with migraine, telcagepant taken daily reduces headache days by 1.4 days per month compared to placebo and causes 2.5% of patients to have elevations of serum ALT levels.

OBJECTIVEHigh triglyceride (TG) levels and low HDL cholesterol (HDL-C) levels are risk factors for cardiovascular disease. It is unclear whether this relationship depends on glycemic dysregulation, sex, or LDL cholesterol (LDL-C) level.RESEARCH DESIGN AND METHODSWe studied 3,216 participants (40% men, 41% with diabetes) who were free of cardiovascular disease at baseline in a community-based, prospective cohort of American Indians (median follow-up 17.7 years). Cox models estimated hazard ratios (HRs) and 95% CIs for incident ischemic stroke and coronary heart disease (CHD) in relation to combined TG and HDL-C status, where a fasting TG level ≥150 mg/dL was “high” and a fasting HDL-C level <40 mg/dL for men (<50 mg/dL for women) was “low.” Models included age, sex, BMI, smoking, diabetes, fasting LDL-C level, antihypertensive medications, physical activity, estimated glomerular filtration rate, and urinary albumin-to-creatinine ratio.RESULTSParticipants with high TG and low HDL levels had a 1.32-fold greater HR (95% CI 1.06–1.64) for CHD than those with normal TG and normal HDL levels. It was observed in participants with diabetes, but not in those without diabetes, that high TG plus low HDL levels were associated with a 1.54-fold greater HR (95% CI 1.15–2.06) for CHD (P value for interaction = 0.003) and a 2.13-fold greater HR (95% CI 1.06–4.29) for stroke (P value for interaction = 0.060). High TG and low HDL level was associated with CHD risk in participants with an LDL-C level of ≥130 mg/dL, but this was not observed in those participants with lower LDL-C levels. Sex did not appear to modify these associations.CONCLUSIONSAdults with both high TG and low HDL-C, particularly those with diabetes, have increased risks of incident CHD and stroke. In particular, those with an LDL-C level ≥130 mg/dL may have an increased risk of incident stroke.

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Background-This study was designed to determine whether overexpression of the enzyme dimethylarginine dimethylaminohydrolase (DDAH) could enhance angiogenesis by reducing levels of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA). Methods and Results-In DDAH1 transgenic (TG) and wild-type mice (each nϭ42), the role of DDAH overexpression on angiogenesis was studied by use of the disk angiogenesis system and a murine model of hindlimb ischemia (each nϭ21). After surgery, animals were treated with either PBS or the NOS inhibitors ADMA or N -nitro-L-arginine methyl ester (L-NAME; each 250 mol · kg Ϫ1 · d Ϫ1 ) by use of osmotic minipumps (each nϭ7). L-NAME was chosen to study an inhibitor that is not degraded by DDAH. Neovascularization in the disk angiogenesis system was impaired by both NOS inhibitors; however, TG animals were resistant to the effects of ADMA on neovascularization. Similarly, TG mice were more resistant to the inhibitory effect of ADMA on angioadaptation (angiogenesis and arteriogenesis) after hindlimb ischemia, as assessed by fluorescent microsphere studies and postmortem microangiograms. Enhanced neovascularization and limb perfusion in TG mice were associated with reduced plasma and tissue ADMA levels and enhanced tissue NOS enzyme activity. Conclusions-We describe a novel mechanism by which DDAH regulates postnatal neovascularization. Therapeutic manipulation of DDAH expression or activity may represent a novel approach to restore tissue perfusion. (Circulation.