ASYMMETRIC DIMETHYL ARGININE (ADMA)

M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Research Scholar

INTRODUCTION

The endothelium play a crucial role in the regulation of vascular tone and structure and its dysfunction is or integral part of the processes leading to atherosclerosis

A symmetric dimethyl arginine (ADMA) is an endogenous

competitive inhibitor of nitric oxide synthase and an important

cause of endothelial dysfunction

ARGININE
Basic semi-essential amino acid Glucogenic Sources : Exogenous sources - Plant sources - Animal sources - Endogenous sources

ENDOGENOUS SOURCE OF ARGININE : UREA CYCLE

ADMA SYNTHESIS Is a metabolic by product of continual protein modification process is a naturally occurring chemical found in blood plasma

The guanidino nitrogen of arginine residuces cretin protein

are methylaled by a group of enzymes called protein arginine

methyl transferases (PRMTS) yielding mono and di-methyl

arginines.

PRMTS (Protein arginine methyl transferases) Are two types - Type 1 PRMTS - Type 2 PRMTS ADMA is the major product of type 1 PRMTS Type1PRMTS: Found mainly in endothelial and smooth muscle cells in cytoplasm of all human cells Type2 PRMTS : Central Nervous System

Synthesis of ADMA

CLEARANCE OF ADMA
Humans generate approximately 300 mol of ADMA/day. A small amount of which (10%) is excreted unchanged into the urine 90% is metabolized by the enzyme dimethyl arginine dimethyl amino hydrolase (DDAH) to yield citrulline and dimethlyamine. DDAH

2 Distinct Isoforms: DDAH-1 DDAH-2

DDAH-1: Found mainly in tissues expressing neuronal nitric oxide synthase Liver Kidney cortex Lung DDAH-2: Found mainly in those tissue expressingendothelial Nos (eNoS) Inducible In endothelium and smooth muscle cells of cardio vascular system Also highly expressed in the kidney

INTERACTIONS

BETWEEN

OXIDATIVE

STRESS,

DIMETHYL

ARGININE,

DIMETHYL AMINO HYDROLASE (DDAH) AND A SYMMETRIC DIMETHYL ARGININE (ADMA) AND NITRIC OXIDE SYNTHASE (NOS).

CLINICAL ASSOCIATIONS

ADMA is associated with cardiovascular risk factors Hypercholesterolaemia ADMA concentrations are increased approximately two fold in diet induced Hypercholesterolaemia LDL cholesterol >4.1mmol/L was associated with reduced No synthesis

INSULIN

ADMA play role in insulin resistance and decreased NO availability

help to drive insulin resistance.

Hyper glycerin impairs DDAH activity in human cells Plasma ADMA concentration is increased in patients with type 2 diabetes mellitus.

Chronic kidney Disease (CKD)

Is a risk factor for cardio vascular disease. Plasma ADMA concentration increase patient with end-stage renal failure (ESRF).

Hypertension
In essential hypertension, ADMA concentration is increased two fold and is associated with reduced levels of urinary NO metabolites

ADMA and Cardio Vascular Disease

ADMA concentration is associated with the presence and extent of atherosclerotic vascular disease.

Increased ADMA concentration can predict -Acute coronary events

- Myocardial infarction
- Peripheral arterial disease - Chronic heart failure

ADMA in critical illness ADMA concentration independently predicts mortality in critically ill patients in the intensive care unit (ICU) ADMA contributes to the development of multiple organ failure in critical illness.

EVIDENCE FROM PROSPECTIVE STUDIES SHOWING ADMA AS PROGNOSTIC MARKER

METHODS FOR MEASUREMENT OF ADMA