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microRNA and the Heart
(expansion of the "miRNA and heart disease" subsection that exists within the microRNA main article)

Atypical microRNA (miRNA) expression levels are linked to a range of heart-related defects. miRNAs have been shown to regulate genes involved in the development of cardiovascular conditions. Because miRNAs dictate the expression patterns of heart-related proteins, defects in miRNA expression can be problematic. Cardiac maladies that have been associated with irregular miRNA levels include dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), cardiac fibrosis (CF), and congestive heart failure (CHF).

Single miRNAs as well as groups of miRNAs play critical roles in heart development maintenance pathways. Studies focusing on single miRNAs explain the biochemistry of the genes and proteins involved in the affected pathway in cardiomyocytes. Levels of multiple miRNAs in relation to specific diagnoses have also been studied.

Gene regulation by miRNAs is vital for healthy heart function. Studies using mice models identify effects of all heart-regulating miRNAs by deleting a gene in cardiomyocytes essential for miRNA generation, dgcr8. Mice with deletion of dgcr8 were unable to produce mature miRNAs in cardiac tissue and therefore displayed ventricular malfunction and DCM, resulting in premature death. Decreased expression of coregulated miR-1 and miR-133 especially revealed dramatic loss of function of cardiomyocytes.

miRNAs and heart-phenotype relation
Of all 721 identified and sequenced human miRNAs, 81 have been linked to heart-related diseases. Table 1 below outlines cardiac-related phenotypes that have been identified in human or mouse models with atypical levels of the referenced miRNA. The table shows relationships that appear most frequently in research published within the past year (2009-2010). ''Table 1: Identified heart-related roles of various miRNAs from published research studies from 2009-2010. ''

miRNA Roles and Heart Structure
Failing heart tissue undergoes numerous structural changes, dictated by growth factor and transcription factor genes. Certain miRNA expression levels vary in patients diagnosed with cardiovascular diseases such as DCM and hypertrophic human hearts – two heart conditions that result from enlargement of cardiac tissue.

miRNA-133 and miRNA-30 limit the expression of growth factor proteins that contribute to fibrosis by binding to connective tissue growth factor (CTGF) – a protein that promotes extracellular growth. Low levels of miRNA-133 and miRNA-30 lead to an overexpression of CTGF, promoting cardiac fibrosis and therefore heart disease. miRNA-208 binds to negative regulators of muscle growth. Overexpression of miRNA-208 therefore induces fibrosis and likelihood of heart failure.

Significant changes in levels of miRNA-21 and miRNA-320 have been identified in human and animal models subject to acute myocardial infarction. miRNA-21 is down-regulated in infected areas. Expression of miR-21 and miR-320 reduce the related rate of cell apoptosis in tissue that has experienced a decrease in blood flow. A decrease in microRNA-320 leads to a protective method for promoting growth of surrounding unaffected cells. Individuals with highly expressed levels of miRNA-320 have an increased susceptibility to infarction. A drug that would knockdown the gene for miRNA-320 proposes a potential for therapy.

miRNA levels measured from heart tissue samples of DCM diagnosed patients revealed a unique miRNA expression pattern in individuals suffering from heart failure. miRNA levels in hearts of DCM patients were compared to those of healthy hearts obtained from transplant donors. Identification of eight atypically expressed miRNAs suggests the existence of a regulatory miRNA network causing altered stimuli to the heart, resulting in DCM.

miRNA Levels and Heart Metabolism
Irregular growth patterns and cardiomyocyte metabolism perturb mechanics of the heart, leading to cardiac disorders such as DCM, CHF, and left ventricular hypertrophy (LVH).

miRNA-133 blocks translation of glucose transportation protein GLUT4, thereby affecting the how energy is supplied to cardiac tissue. Overexpression of miRNA-133 can worsen the effect of tissue damage by failing to respond to the severe decrease in available chemical energy.

The miRNA-208a regulates cardiac conduction through its role in the ATP conversion pathway. Disturbance in the energy-conversion pathway is associated with hypertrophic cardiomyopathies and heart failure.

Potential Applications and Cardiac Therapies
Knowledge of miRNA functions may lead to the development of novel therapies and identification markers for heart-related disorders. Gene therapies would seek to develop ways to directly manipulate miRNA levels in heart tissue.

Therapies promoting overexpression of miRNA-133 may prevent overgrowth of cardiac tissue and fibrosis to regulate normalcy in the electromechanical potential and functional structure of the heart.

The research community has responded to increasing investigations in the potential miRNA therapies through conferences and talks. The annual microRNA in Human Disease and Development conference hosted by the Cambridge Healthtech Institute included talks on the potential of miRNA manipulation strategies as treatments for cardiovascular diseases.