Role of MicroRNA-424(322)/503 in Heart Disease

Background: Cardiovascular disease is the topmost cause of death globally. Dilated cardiomyopathy (DCM), the most common cardiovascular diseases, is characterized by chamber dilation and systolic dysfunction eventually leading to heart failure. MicroRNAs have been shown to play an integral role in regulating the progression of cardiomyopathy and as a result have become novel targets for therapy. Previously, we found that miR-424(322)/503 is highly enriched in embryonic heart during early cardiac development but its expression drops to very low level after birth. Interestingly, other studies have revealed its upregulation in failing human hearts. However, the relation between miR-424(322)/503 and heart failure is not yet known. Methods and results: To understand the role of miR-424(322)/503 in the adult heart, we generated a tetracycline-controlled cardiomyocyte-specific miR-424(322)/503 expressing transgenic mice (TG). miR-424(322)/503 was induced in TG and wildtype (WT) mice (8 weeks) using doxycycline containing chow continuously for a month. The cardiac function was monitored every week. The tissues were harvested at the endpoint of the study for downstream analysis. We observed that the heart function of TG started deteriorating from 2 weeks of miR-424(322)/503 induction. Cardiac failure markers (ANP and BNP) were upregulated. Histology revealed dilated chambers with thin ventricular wall, presence of fibrosis and disorganized myocytes in TG, a phenotype consistent with DCM. We also observed that miR-424(322)/503-induced DCM progressed slowly with intermittent dose and even slower with lower dose of doxycycline. To further study the causative role, we removed the miR-424(322)/503 induction after 14 days and let them recover. We found that miR-424(322)/503-induced heart failure could be reversed by interrupting miR-424(322)/503 induction. RNA sequencing was done next to determine the genome-wide transcriptional changes. We observed several mitochondria-related genes and pathways to be downregulated. We also found mitochondrial dysregulation to be the common pathway between miR-424(322)/503-induced heart failure and human heart failure. Conclusion: Overall, this is the first study to show that upregulated miR-424(322)/503 in the heart is sufficient to lead to DCM and miR-424(322)/503-induced heart failure is reversible. We hypothesized that miR-424(322)/503-triggered DCM by dysregulating mitochondria. Thus, this study supports miR-424(322)/503 as a novel potential therapeutic target for DCM and heart failure

Role of MicroRNA-424(322)/503 in Heart Disease

Background: Cardiovascular disease is the topmost cause of death globally. Dilated cardiomyopathy (DCM), the most common cardiovascular diseases, is characterized by chamber dilation and systolic dysfunction eventually leading to heart failure. MicroRNAs have been shown to play an integral role in regulating the progression of cardiomyopathy and as a result have become novel targets for therapy. Previously, we found that miR-424(322)/503 is highly enriched in embryonic heart during early cardiac development but its expression drops to very low level after birth. Interestingly, other studies have revealed its upregulation in failing human hearts. However, the relation between miR-424(322)/503 and heart failure is not yet known. Methods and results: To understand the role of miR-424(322)/503 in the adult heart, we generated a tetracycline-controlled cardiomyocyte-specific miR-424(322)/503 expressing transgenic mice (TG). miR-424(322)/503 was induced in TG and wildtype (WT) mice (8 weeks) using doxycycline containing chow continuously for a month. The cardiac function was monitored every week. The tissues were harvested at the endpoint of the study for downstream analysis. We observed that the heart function of TG started deteriorating from 2 weeks of miR-424(322)/503 induction. Cardiac failure markers (ANP and BNP) were upregulated. Histology revealed dilated chambers with thin ventricular wall, presence of fibrosis and disorganized myocytes in TG, a phenotype consistent with DCM. We also observed that miR-424(322)/503-induced DCM progressed slowly with intermittent dose and even slower with lower dose of doxycycline. To further study the causative role, we removed the miR-424(322)/503 induction after 14 days and let them recover. We found that miR-424(322)/503-induced heart failure could be reversed by interrupting miR-424(322)/503 induction. RNA sequencing was done next to determine the genome-wide transcriptional changes. We observed several mitochondria-related genes and pathways to be downregulated. We also found mitochondrial dysregulation to be the common pathway between miR-424(322)/503-induced heart failure and human heart failure. Conclusion: Overall, this is the first study to show that upregulated miR-424(322)/503 in the heart is sufficient to lead to DCM and miR-424(322)/503-induced heart failure is reversible. We hypothesized that miR-424(322)/503-triggered DCM by dysregulating mitochondria. Thus, this study supports miR-424(322)/503 as a novel potential therapeutic target for DCM and heart failure

Cardiomyopathy Progression Due to Overexpression of miRNA- 322/503

Dilated cardiomyopathy is the leading cause of death among heart disease patients. It is characterized by a decrease in blood flow through the heart due to enlargement and weakness of the left ventricle. The miRNA, mir-322/503, was found to be increased in expression in dilated cardiomyopathy. Our lab has found that overexpression of miRNA- 322/503 in the heart using a doxycycline induced mouse model, leads to heart failure that exhibits characteristics of dilated cardiomyopathy. The main objective of this research was to monitor this heart failure progression over time. In vivo mice models were given a doxycycline diet for a month and body weight was monitored. Heart specific tissues were collected at days 0, 7, 14, 21 and 28 and stained with H&E stain. Heart stress markers were analyzed using qPCR. We found overexpression of miRNA- 322/503 leads to body weight loss, loss of cardiac function through dilation of ventricular chambers and wall thinning, increase in stress markers ANP (Atrial natriuretic peptide) and BNP (Brain natriuretic peptide), and a decrease in α-MHC (Myosin heavy chain).Biomedical Engineering, Department ofHonors Colleg

Microbial Enzymes Used in Bioremediation

Emerging pollutants in nature are linked to various acute and chronic detriments in biotic components and subsequently deteriorate the ecosystem with serious hazards. Conventional methods for removing pollutants are not efficient; instead, they end up with the formation of secondary pollutants. Significant destructive impacts of pollutants are perinatal disorders, mortality, respiratory disorders, allergy, cancer, cardiovascular and mental disorders, and other harmful effects. The pollutant substrate can recognize different microbial enzymes at optimum conditions (temperature/pH/contact time/concentration) to efficiently transform them into other rather unharmful products. The most representative enzymes involved in bioremediation include cytochrome P450s, laccases, hydrolases, dehalogenases, dehydrogenases, proteases, and lipases, which have shown promising potential degradation of polymers, aromatic hydrocarbons, halogenated compounds, dyes, detergents, agrochemical compounds, etc. Such bioremediation is favored by various mechanisms such as oxidation, reduction, elimination, and ring-opening. The significant degradation of pollutants can be upgraded utilizing genetically engineered microorganisms that produce many recombinant enzymes through eco-friendly new technology. So far, few microbial enzymes have been exploited, and vast microbial diversity is still unexplored. This review would also be useful for further research to enhance the efficiency of degradation of xenobiotic pollutants, including agrochemical, microplastic, polyhalogenated compounds, and other hydrocarbons