Biochemistry_of_the_Heart_FA23.V1 (1).pptx

Biochemis try of the Heart VA N E S S A D E L A R O S A , PHD CVI • Overview energy metabolism in the heart, including the phosphocreatine shuttle. • Explain the “adenosine hypothesis” and relate this information to its cardiovascular effects. • Discuss cardiolipin and integrate its unusual synth...

Biochemis try of the Heart VA N E S S A D E L A R O S A , PHD CVI • Overview energy metabolism in the heart, including the phosphocreatine shuttle. • Explain the “adenosine hypothesis” and relate this information to its cardiovascular effects. • Discuss cardiolipin and integrate its unusual synthesis and structure with its roles in physiological and pathophysiological processes of the heart. Session Objectives • Discuss the role of oxidative stress in cardiovascular disease, such as acute myocardial infarction, congestive heart failure, and myocardial necrosis. • Review advanced glycation end-products (AGEs) and integrate with the cardiovascular complications of diabetes. • Review inhibition of eicosanoid synthesis by aspirin and relate this information to its cardioprotective effects. • Identify existing and selected emerging biochemical markers of cardiovascular disease, including cardiac troponins, creatine kinase, myoglobin, natriuretic peptides, C-reactive protein, and myeloperoxidase. Hypoxia Overvie w •The heart can use all classes of energy substrates for ATP production •Lots of mitochondria (heart consumes more oxygen than any other organ) •Mitochondrial ATP synthesis is matched by cytosolic ATP consumption Normoxi a •ATP drives heart contraction & fuels ion pumps that allow for diastolic relaxation Regulation of cardiac metabolism Transcriptional regulation of lipid metabolism by peroxisome proliferator-activated receptor α (PPARα) important for adaptation to chronic metabolic disease Transcriptional regulation by hypoxia-inducible factor-1α is responsible for the adaptation to hypoxic and ischemic conditions. Characteristics of fuel metabolism under normal conditions Heart stores fuel in the form of glycogen and triacylglycerol (TG) Cardiomyocytes depend on delicate balance of glucose and fatty acid as energy sources dependent on oxygen conditions Primarily rely on oxidative metabolism, particularly in fasted state (fueled by fatty acids) β-oxidation generates lots of reducing equivalents & feeds TCA cycle & ETC Stores of glycogen are low Mitochondrial ATP synthesis is matched by cytosolic ATP consumption Cardiomyocyte Metabolism under hypoxic conditions • Characterized by substantially reduced O2 delivery to tissues/cells • Limitations in O2 decrease electron flow through the ETC & the production of ATP • Anaerobic glycolysis cannot meet tissue/cell energy demand, especially nerves & cardiac muscle Phosphocreatine shuttle • Moves high-energy phosphate from mitochondrial site of production to cytoplasmic sites of utilization (primarily contractile apparatus in heart) • Involves different CK isoforms with defined subcellular locations • mitochondrial CK isoform (MiCK; localized to intermembrane space) converts ATP (+ creatine) produced by oxidative phosphorylation to PCr (+ ADP) • myofibrillar CK isoform (MMCK; localized to myofibrils) converts PCr (+ADP) produced during contraction to ATP (+ creatine) • PCr diffuses from mitochondria to myofibrils and creatine diffuses back • Pathological cardiac hypertrophy  decreased PCr/ATP ratio why might this be important Metabolic reprogram ming • Cardiac metabolism undergoes a reprogramming in response to pathological hypertrophy • Chronic metabolic adaptations reflect alterations in gene expression Pressure-overload hypertrophy (LVH) & dilated cardiomyopathy Diabetes mellitus ↑ PPARα ↓ PPARα up-regulation of βoxidation genes down-regulation of βoxidation genes down-regulation of glucose use up-regulation of glucose use Metabolic remodeling summary Adenosine hypothesis Myocardial hypoxia leads to the breakdown of adenine nucleotides and formation of adenosine Adenosine diffuses out of cardiac myocyte & causes arteriolar dilation Front. Physiol., 20 October 201 Cardiovascular effects of adenosine •Helps regulate cardiac function, including heart rate, contractility, and coronary flow •ATP production & oxygen supply must closely match across broad range of work loads •myocardial ATP content lower (4–6 μmol/g) than basal rate of use (30 μmol/g/minute) •Adenosine rapidly produced in cardiac myocyte when energy supply < energy demand •Decreased intracellular Ca2; leads to relaxation, vasodilatation, & ↑ coronary blood flow Cardiolipin •Phospholipid (PL) abundant in heart Nascent CL •Only PL synthesized in mitochondria •Remodeled after synthesis by taffazin (a transacylase) •Atypical structure contains 3 glycerol backbones and 4 fatty acyl chains •All acyl chains are linoleic acid Mature CL Saric A, Andreau K, Armand A-S, Møller IM and Petit PX (2016) Barth Syndrome: From Mitochondrial Dysfunctions Associated with Aberrant Production of Reactive Oxygen Species to Pluripotent Stem Cell Studies. Front. Genet. •Facilitates ATP synthesis by organizing inner mitochondrial membrane lipids & proteins Cardiolipin and ATP production • Cardiolipin structure impacts mitochondrial ATP synthesis Phosphate head group forms bicyclic resonance structure that traps protons • Cardiolipin maintains the structure of the mitochondrial inner membrane Saric A, Andreau K, Armand A-S, Møller IM and Petit PX (2016) Barth Syndrome: From Mitochondrial Dysfunctions Associated with Aberrant Production of Reactive Oxygen Species to Pluripotent Stem Cell ROS Inherited and Acquired Disorders of Cardiolipin Barth syndrome (X-linked recessive disorder) • Defect in taffazin gene • Presents with symptoms primarily related to an “energy deficit” • myopathy (skeletal muscle weakness) and often cardiomyopathy, neutropenia, growth delay Antiphospholipid syndrome (APS) • Acquired autoimmune disorder of hypercoagulation • Antibodies produced that react with cardiolipin (& other lipids) • Predisposes to clotting, predominantly by interfering with antithrombotic role of phospholipids Oxidative stress and cardiovascular disease •Reactive oxygen species (ROS) exert toxic effects in heart •Results in mitochondrial dysfunction mitochondrial proteins, lipids, and mtDNA become dysfunctional Oxidative stress increases susceptibility to: •acute myocardial infarction (AMI) •congestive heart failure •myocardial necrosis resulting from lipid peroxidation Advanced Glycation End-Products (AGEs) •AGEs are nonenzymatically glycated & oxidized proteins/lipids •Alter protein/lipid structure & function •AGEs are prevalent in diabetic vasculature & promote development of atherosclerosis Remember from M2P? Trends in Endocrinology & Metabolism, 2019-12-01, Volume 30, Issue 12, Pages 959-973 Biomarkers of disease I NTRACEL LUL A R ENZ Y MES A ND PR OT EINS I N D I C AT E C E L LU L A R O R T I S S U E D A M A G E A R E U S E F U L F O R I N D I C AT I N G D I S E A S E cardiac troponins: troponin T (cTnT) & troponin I (cTnI) isoforms Biomarkers of cardiac disease • Cardiac troponins preferred biomarker to detect myocardial injury • TnT most common marker used to evaluate acute MI & risk-stratification in acute coronary syndromes (ACS) • Cardiac troponin levels begin to increase 4 to 6 h after the onset of chest pain. • Creatine kinase MB (CK-MB) cytosolic isoform • lower sensitivity & specificity compared to troponins • more useful for detecting additional cardiac muscle injury over time • Myoglobin • Released quickly Cardiovascular effects of aspirin • Used (at lower doses) to prevent and treat CVD • Irreversibly inhibits cyclooxygenase 1 (COX1) • Inhibits synthesis of pro-inflammatory eicosanoids More on this in Resp I…