Galectin-3: A Risk-Predictor of Sudden Cardiac Arrest

Introduction:

Cardiac biomarkers are measured to evaluate heart function. To monitor the progress of the disease, we need cardiac biomarkers. Most markers identified are enzymes and proteins. Ideal molecular biomarkers, sensitive and specific to heart disease, are likely to provide a much earlier diagnosis, thereby providing better treatment outcomes. Galectin-3 is expressed in various immune cells and plays a significant role in many physiological functions. Galectin-3 is expressed readily on the cell surface and secreted by injured and inflammatory cells. Cardiac galectin-3 is a marker for cardiac disorders such as cardiac inflammation and fibrosis, depending on the specific pathogenesis. So galectin-3 is a novel candidate biomarker for diagnosing and prognosis of many heart diseases such as heart failure. Heart disease treatment aims to prevent the acute onset and predict its occurrence using the ideal molecular biomarkers. This article describes galectin-3 as a next-generation molecular biomarker of heart disease. Furthermore, galectin-3 may be useful as a diagnostic marker for detecting the early stages of various heart diseases, which may contribute to improved early therapeutic interventions.

What Is Galectin-3?

Galectin-3 is:

• Lectins are carbohydrate-binding proteins present in plants and animals.

• Galectins belong to the family of animal lectins. They are a group of water-soluble, non-glycosylated globular proteins that interact with carbohydrates independently.

• Galectins are synthesized in the cytoplasm.

• They are secreted in the outer plasma membrane and the extracellular matrix (ECM) and are in circulation.

• Galectin-3 is a β-galactoside-binding lectin that belongs to the galectin family. Galectin 3 binds proteins in a carbohydrate-dependent and independent manner.

• Galectin-3 is predominantly located in the cytoplasm, but it shuttles into the nucleus and is secreted onto the cell surface and into biological fluids, including serum and urine.

• It serves important functions in numerous biological activities such as cell growth, apoptosis (programmed cell death), pre-mRNA splicing (RNA splicing is a process in molecular biology where a newly made precursor messenger RNA transcript is transformed into a mature messenger RNA), differentiation (the process by which immature cells become mature cells), transformation, angiogenesis (formation of new blood vessel cells), inflammation, fibrosis, and host defense.

• Cardiac markers are proteins released from injured myocardial (heart muscle) cells through damaged cell membranes into the bloodstream. Doctors or physicians measure cardiac enzymes through enzyme marker tests (blood tests).

• The enzymes, hormones, biological substances, and myocytic injury that increase in their levels in response to cardiac stress or disease are called biomarkers.

• Galectin-3 is a diagnostic and prognostic biomarker of heart disease, kidney disease, and cancer.

• Galectin-3 is widely expressed in human tissues. It is present in all immune cells, such as macrophages, monocytes, dendritic cells, eosinophils, mast cells, natural killer cells, and activated T and B cells. It is found in epithelial cells, endothelial cells, and sensory neurons.

• The expression of galectin-3 in tissues is developmentally regulated; it is more abundant during embryogenesis compared with adult life.

• During the early stages of embryogenesis, its expression pattern is more specific, located predominantly in the epithelium, kidney, chondrocytes, and liver.

What Is the Significance of Cardiac Biomarkers in the Management of Cardiovascular Diseases?

Cardiovascular diseases are the leading cause of death globally. Individuals at risk of heart disease demonstrate elevated body weight, blood pressure, plasma cholesterol, blood glucose, and obesity. They can easily be diagnosed in primary healthcare services and provide efficacious therapeutic interventions. Detecting ideal molecular biomarkers that are sensitive and specific to heart disease is likely to provide an early diagnosis and suggest targeted therapy. Cardiac biomarkers help doctors and physicians discover the causative factor and symptoms of heart attack, angina, heart failure, and myocardial infarction and provide appropriate treatment to prevent further complications.

• Screening test for heart disease.

• Monitors the efficacy of heart surgery and cardiovascular medications.

• Diagnosis of chest pain and breathlessness.

Why Does Cardiac Fibrosis Happen in Heart Failure?

The mechanism of cardiac fibrosis in heart failure is:

• Heart failure is caused by myocardial infarction (blockage of blood flow to the heart muscle). Following myocardial infarction, the cardiac cells die due to ischemia (poor oxygen supply to the tissues).

• Fibrotic scars replace dead cells because the heart cannot regenerate after an injury. Ischaemic cell death after a myocardial infarction leads to repair in the affected area. The pathologic changes in heart failure occur in two steps.

• One is cardiomyocyte (heart muscle cell) hypertrophy (increase in the size of the heart muscle), necrosis (premature death of the cells), and apoptosis (programmed cell death), and the other is cardiac fibroblast hyperplasia and cardiac fibrosis.

• Cardiac fibrosis is an important feature in the mechanism of heart failure.

• Myocardial death leads initially to an inflammatory response where granulocytes, macrophages, and fibroblasts are recruited to the region of injury. This area is ultimately replaced by secreted ECM (extracellular matrix proteins) proteins such as collagen to form scar tissue.

• Reparative scar formation is beneficial in replacing dead cardiomyocytes, preventing myocardial rupture, and maintaining myocardial continuity.

• Myocardial fibrosis is the expansion of the cardiac interstitium by depositing extracellular matrix proteins. Activated fibroblasts and myofibroblasts are the main factors in cardiac fibrosis. Cardiac cells, known as cardiomyocytes, and the immune cells and vascular cells acquire a change because of stress.

• Fibrogenic growth factors such as cytokines, tumor necrosis factor, and interleukin trigger the fibrogenic signaling cascades by binding through the surface receptors of the myocardium. The matrix metalloproteins are deposited in the myocardium and regulate matrix assembly.

• Fibrosis results in the accumulation of extracellular matrix (ECM) at the injury site and the scar's production. During cardiac damage and stress, various fibroblasts differentiate into myofibroblasts. Myocardial remodeling is associated with myocardial stiffness and contributes to heart failure.

How Is Galectin-3 an Important Biomarker in Heart Failure?

The importance of galectin-3 as a biomarker is:

• Gal-3 (galectin-3) is a member of a β-galactoside–binding lectin family, expressed in inflammatory cells, cardiac and vascular cells, kidney, and adipose tissue.

• Gal-3 levels are increased in the myocardium and plasma of heart failure patients.

• Gal-3 is a biomarker of cardiac fibrotic degeneration in animal models. Serum Galectin-3 has been used as an early diagnostic biomarker for detecting cardiac degeneration in acute myocarditis and myocardial infarction.

• In addition to heart disease, Gal-3 has also been considered a biomarker in other human diseases, such as viral infections, autoimmune diseases], diabetes, kidney diseases, and even tumor formations, including thyroid tumors. The evidence suggests that Gal-3 is not an organ-specific marker but a specific marker of individual pathogenesis, such as inflammation or fibrosis.

• A high concentration of plasma Gal-3 correlates with a clinical outcome in heart failure associated with cardiac fibrosis.

• The increased plasma levels of Gal-3 are associated with adverse long-term cardiovascular outcomes in patients with acute heart failure.

• Some evidence shows plasma Gal-3 in the general population revealed that elevated plasma galectin-3 is associated with a high risk of cardiovascular mortality and heart failure, in addition to all-cause mortality, and has suggested that galectin-3 is an important prognostic factor for patients with heart disease.

What Is the Role of Galectin-3 in Atherosclerosis?

The role of galectin-3 in atherosclerosis is:

• Atherosclerosis is a disease where plaque builds up on the intima and medial layers of walls of the arteries (blood vessels). Blood vessels deliver blood and oxygen from the heart to the rest of the body.

• Atherosclerosis is a plaque of cholesterol and other substances in the artery walls. The fibrofatty plaque causes the arteries to narrow, blocking blood flow and leading to a blood clot.

• Galectin-3 is a potent inflammatory protein that contributes to the inflammatory response related to acute and chronic inflammation.

• The subsequent inflammatory response involves the massive participation of monocytes and macrophages, altering the structure of the intima and media layers of the blood vessel wall.

• Endothelial cells become activated, producing an extracellular matrix. The narrowing of the artery lumen leads to a decreased blood flow that can be completely arrested in case of a thrombus (blood clot) formation on the plaque surface, causing acute events such as acute myocardial infarction (AMI) or stroke.

• The involvement of many inflammatory markers in the atherosclerotic process has been investigated over the years, and a potential role of Gal-3 as a mediator for atherosclerosis has been identified.

• A higher concentration of Galectin-3 is detected in foam cells and macrophages of atherosclerotic lesions.

What Is the Mechanism of Galectin-3 in Cardiac Fibrosis in Heart Failure Patients?

The mechanism of galectin-3 in cardiac fibrosis is:

• Galectin-3 expression is associated with abundant macrophages, increased fibroblast activity, accumulation of extracellular matrix, and collagen production in the myocardium. Fibroblasts and macrophages also express the protein following stressful events.

• The galectin-3 increase was evidenced in rat models after myocardial infarction. Rats infused with Galectin-3 reported enhanced macrophage and mast cell infiltration, increased cardiac interstitial and perivascular fibrosis, and cardiac hypertrophy.

• After its activation, Galectin-3 forms a lattice complex entrapping TGFβ on the cell surface, giving a prolonged signal of fibrotic development. These signaling factors and mechanical stress transform quiescent fibroblasts into active collagen-producing myofibroblasts.

• Galectin-3 is involved in the pathophysiology of heart failure mainly because of its role in cardiac ventricular remodeling.

• Galectin-3 expression in the heart is low, whereas its synthesis and secretion increase in heart failure. Galectin-3 initially plays a protective role in the heart through its anti-apoptotic and anti-necrotic functions.

• At the same time, the prolonged expression of this protein leads to fibrosis and adverse remodeling of the damaged tissue. Galectin-3 binding sites are mainly localized in the myocardial matrix, fibroblasts, and macrophages.

• At the injury site, Galectin-3 is secreted into the extracellular space, activating resting fibroblasts into matrix-producing fibroblasts. The role of Gal-3 in fibroblast activation involves up-regulation of the cytoskeletal proteins and the synthesis of new matrix components such as type I collagen.

• Moreover, another study showed that Galectin-3 infusion caused myocardial fibrosis, which was neutralized by an anti-fibrotic agent, suggesting that Galectin-3 may be involved in developing and resolving fibrosis.

• In a rat model of hypertensive heart failure, recombinant Galectin-3 infusion into the pericardial sac for four weeks induced excessive collagen deposition and cardiac dysfunction, which is likely to develop into heart failure.

Conclusion:

Gal-3 is an active player in fibrosis development, the atherosclerotic process, and inflammation-based diseases in cardiovascular diseases. The most prominent aspect of this molecule is that it can be successfully used as a risk marker of cardiovascular diseases if measured in plasma.