Antioxidant Therapy Attenuates Post-Infarct Cardiac Remodeling by Driving Expression of Krüppel-Like Factor 15

Background: Myocardial infarction (MI) results in severe biochemical, physiological, and cellular changes that lead to alterations in the structure and function of the myocardium. Oxidative stress potentiates this remodeling response and is associated with progressive worsening of cardiac function. Accordingly, we used a powerful antioxidant-based therapeutic strategy to improve cardiac health and study redox-dependent signaling. Methods: MI was surgically induced in rats by ligating the left anterior descending coronary artery. Subgroups of MI rats received resveratrol (i.p., 10 mg/kg/day for 28 days beginning immediately post-MI). Cardiac histology and biochemical analyses of genes and proteins implicated in cardiac fibrosis, hypertrophy, and apoptosis, and redox-dependent signaling were analyzed. Results: As expected, MI resulted in profound structural changes to the myocardium. Further, we observed a sharp reduction in nuclear factor-erythroid 2-related factor 2 (Nrf2) and Krüppel-like factor 15 (KLF15), factors that are responsible for maintaining the endogenous antioxidant capacity and regulating cardiac gene expression, respectively. It is likely that disruption of normal KLF15 signaling permitted the expression of several cardiac genes associated with progressive cardiac remodeling. Importantly, daily treatment with resveratrol ameliorated cardiac remodeling, improved redox state, restored Nrf2 expression, and up-regulated KLF15 expression. Further, induction of KLF15 signaling following resveratrol treatment is associated with attenuated expression of several genes implicated in cardiac remodeling. Conclusions: Chronic oxidative stress potentiates cardiac remodeling post-infarct, in part, by suppressing Nrf2 and KLF15 expression. Importantly, we demonstrate that normal KLF15 signaling may be rescued with an antioxidant-based therapy, which may be an attractive therapeutic target to support cardiac health post-MI

Antioxidant Therapy Attenuates Post-Infarct Cardiac Remodeling by Driving Expression of Krppel-Like Factor 15

Background: Myocardial infarction (MI) results in severe biochemical, physiological, and cellular changes that lead to alterations in the structure and function of the myocardium. Oxidative stress potentiates this remodeling response and is associated with progressive worsening of cardiac function. Accordingly, we used a powerful antioxidant-based therapeutic strategy to improve cardiac health and study redox-dependent signaling. Methods: MI was surgically induced in rats by ligating the left anterior descending coronary artery. Subgroups of MI rats received resveratrol (i.p., 10 mg/kg/day for 28 days beginning immediately post-MI). Cardiac histology and biochemical analyses of genes and proteins implicated in cardiac fibrosis, hypertrophy, and apoptosis, and redox-dependent signaling were analyzed. Results: As expected, MI resulted in profound structural changes to the myocardium. Further, we observed a sharp reduction in nuclear factor-erythroid 2-related factor 2 (Nrf2) and Krüppel-like factor 15 (KLF15), factors that are responsible for maintaining the endogenous antioxidant capacity and regulating cardiac gene expression, respectively. It is likely that disruption of normal KLF15 signaling permitted the expression of several cardiac genes associated with progressive cardiac remodeling. Importantly, daily treatment with resveratrol ameliorated cardiac remodeling, improved redox state, restored Nrf2 expression, and up-regulated KLF15 expression. Further, induction of KLF15 signaling following resveratrol treatment is associated with attenuated expression of several genes implicated in cardiac remodeling. Conclusions: Chronic oxidative stress potentiates cardiac remodeling post-infarct, in part, by suppressing Nrf2 and KLF15 expression. Importantly, we demonstrate that normal KLF15 signaling may be rescued with an antioxidant-based therapy, which may be an attractive therapeutic target to support cardiac health post-MI

Eccentric Contractions Disrupt FKBP12 Content in Mouse Skeletal Muscle

Strength deficits associated with eccentric contraction-induced muscle injury stem, in part, from impaired voltage-gated sarcoplasmic reticulum (SR) Ca2+ release. FKBP12 is a 12-kD immunophilin known to bind to the SR Ca2+ release channel (ryanodine receptor, RyR1) and plays an important role in excitation-contraction coupling. To assess the effects of eccentric contractions on FKBP12 content, we measured anterior crural muscle (tibialis anterior [TA], extensor digitorum longus [EDL], extensor hallucis longus muscles) strength and FKBP12 content in pellet and supernatant fractions after centrifugation via immunoblotting from mice before and after a single bout of either 150 eccentric or concentric contractions. There were no changes in peak isometric torque or FKBP12 content in TA muscles after concentric contractions. However, FKBP12 content was reduced in the pelleted fraction immediately after eccentric contractions, and increased in the soluble protein fraction 3 day after injury induction. FKBP12 content was correlated (P = 0.025; R2 = 0.38) to strength deficits immediately after injury induction. In summary, eccentric contraction-induced muscle injury is associated with significant alterations in FKBP12 content after injury, and is correlated with changes in peak isometric torque

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial

Background After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1.4-1.8 mmol/L with ezetimibe or statins reduces cardiovascular events in patients with an acute coronary syndrome and diabetes. However, the efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. We aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycaemic status, while also assessing its effects on glycaemic measures including risk of new-onset diabetes

Apolipoprotein B, Residual Cardiovascular Risk After Acute Coronary Syndrome, and Effects of Alirocumab.

Background: Apolipoprotein B (apoB) provides an integrated measure of atherogenic risk. Whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndrome beyond that provided by low-density lipoprotein cholesterol is uncertain. Methods: The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin therapy. Primary outcome was major adverse cardiovascular events (MACE; coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, hospitalization for unstable angina). Associations between baseline apoB or apoB at 4 months and MACE were assessed in adjusted Cox proportional hazards and propensity score–matched models. Results: Median follow-up was 2.8 years. In proportional hazards analysis in the placebo group, MACE incidence increased across increasing baseline apoB strata (3.2 [95% CI, 2.9–3.6], 4.0 [95% CI, 3.6–4.5], and 5.5 [95% CI, 5.0–6.1] events per 100 patient-years in strata 35–<50, and ≤35 mg/dL, respectively). Compared with propensity score–matched patients from the placebo group, treatment hazard ratios for alirocumab also decreased monotonically across achieved apoB strata. Achieved apoB was predictive of MACE after adjustment for achieved low-density lipoprotein cholesterol or non–high-density lipoprotein cholesterol but not vice versa. Conclusions: In patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, MACE increased across baseline apoB strata. Alirocumab reduced MACE across all strata of baseline apoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved apoB was associated with lower risk of MACE, even after accounting for achieved low-density lipoprotein cholesterol or non–high-density lipoprotein cholesterol, indicating that apoB provides incremental information. Achievement of apoB levels as low as ≤35 mg/dL may reduce lipoprotein-attributable residual risk after acute coronary syndrome. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01663402.gov; Unique identifier: NCT01663402.URL: https://www