Atrasentan-based therapy for Cardiac repair and myocardial infarction: Atrasentan, a drug used in the treatment of cancer,  pulmonary hypertension and others, increases Agrin expression, activates Yap and ERK-mediated signaling,  replaces scar tissue with functional cardiomyocytes, and promotes cardiomyocyte regeneration and repair after myocardial infarction, via up-regulation of its target gene, 10/May/2019,  11.48 pm

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Introduction: What they say:

A recent study from Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel; Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA; and Baylor College of Medicine and The Texas Heart Institute, Houston, Texas 77030, US shows that The extracellular matrix protein Agrin promotes heart regeneration in mice.” This study was published, in the 5 June 2017 issue of Nature, by Prof Tzahor E, Bassat E and others.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Atrasentan-based therapy for Cardiac repair and myocardial infarction: Atrasentan, a drug used in the treatment of cancer,  pulmonary hypertension and others, increases Agrin expression, activates Yap and ERK-mediated signaling,  replaces scar tissue with functional cardiomyocytes, and promotes cardiomyocyte regeneration and repair after myocardial infarction, via up-regulation of its target gene


From Significance of the study to Public Health Relevance:

Given that: (1) cardiovascular disease is the leading cause of death worldwide; (2) the raise of death rate, due to cardiovascular disease, has increased from 123 lakhs in 1990 to 173 lakhs in 2013; (3) 85% of people over 80 years are susceptible to cardiovascular diseases;(4) in India, in 2004, 14.6 lakhs deaths (14% of total deaths) were due to ischemic heart disease; (3) the death due to cardiovascular disease is higher in low-to-middle income countries compared to developed countries; (4) the global economic cost spent in the treatment of cardiovascular disease in 2011 was little more than 10 billion US dollars; (5) an alarming number of people, such as 230 lakhs people, will die from cardiovascular diseases each year by 2030, there is an urgent need to find: (i) a way to induce regeneration of cardiomyocytes that were lost in Myocardial patients; (ii) a cheaper alternative to the existing expensive drugs; and (iv) a side-effect-free Natural product-based drug that heals damaged heart tissue.


What is known?

Prof. Tzahor’s research team has shown recently that: (1) Agrin, one of the components of the neonatal Extracellular matrix (ECM) , promotes regeneration in mouse hearts;  and (2) Agrin promotes cardiomyocytes regeneration after heart attack through disruption of dystrophin-glycoprotein complex and activation of Yap and ERK-mediated signaling,  suggesting that activation of Agrin may: (1) replace  the damaged scar tissue, with functional cardiomyocytes, after myocardial infarction; and (2) protect an individual from myocardial infarction through cardiac rejuvenation and regeneration.


From research findings to Therapeutic Opportunity:

I had suggested earlier  on 21/January/2018 at 11.02 pm that Atrasentan  may improve metabolic abnormalities, albuminuria, glomerular pathology, and renal dysfunction and alleviate diabetic nephropathy  (https://genomediscovery.org/2018/01/molecular-therapy-for-diabetic-nephropathy-dn-atrasentan-a-drug-used-in-the-treatment-of-diabetic-kidney-disease-and-cancer-increases-pyruvate-kinase-m2-pkm2-expression-decreases-tox).

Evidently, a very recent study from the Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands and others shows that “Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease. This study was published, in the 12 April 2019 issue of of the prestigious journal Lancet (Impact factor: 53.254),  by Prof. De Zeeuw D, Heerspink HJL, and others. In concordance with what I stated earlier, this study suggests that atrasentan may protect renal function in  patients with type II diabetes .  However, the mechanism of action of this drug is not known yet.  

This study provides, for the first time, mechanistic insights into how Atrasentan, which is used to treat cancer, pulmonary hypertension, diabetic kidney diseases and others, may aid in heart regeneration and repair.

Atrasentan, by decreasing the expression of its target genes, it may increase the expression of Agrin (fig.1). Thereby, it may: (1) inhibit dystrophin-glycoprotein complex;(2) increase Yap and ERK-mediated signaling; (3) increase the expression of gene products that promote cardiac regeneration and survival;(4) increase the expression of miRNAs that promote cardiac regeneration and survival;(5) increase cardiomyocyte proliferation; (6) replace scar tissue with heart muscle functional  cardiomyocytes; (7) promote cardiomyocyte survival/regeneration; (8) promote recovery after myocardial infarction; and (9) extend lifespan (fig 1).

Thus, by treating myocardial patients with Atrasentan or its analogs, cardiologists may preserve myocardial function after myocardial infarction; and prevent ageing-associated (or, stress-associated) decline in cardiac function. Together, this study suggests, for the first time, that pharmacological formulations encompassing “Atrasentan  or its analogs, either alone or in combination with other drugs,” may be used to heal the damaged cardiac tissue after myocardial infarction (fig. 2).

Figure 1. Mechanistic insights into how Atrasentan promotes heart regeneration and repair. Atrasentan induces the expression of Agrin and other genes that promote cardiac regeneration and repair to prevent myocardial infarction and diabetic cardiomyopathy.

Figure 2. Atrasentan-based therapy for myocardial diseases. Atrasentan may aid in heart regeneration and repair through induction of Agrin and other genes.


Details of the research findings:

Idea Proposed/Formulated (with experimental evidence) by:

Dr L Boominathan Ph.D.

Terms & Conditions apply http://genomediscovery.org/registration/terms-and-conditions/

Undisclosed mechanistic information: How atrasentan increases the expression of Agrin and promotes cardiac regeneration and repair

Amount: $ 500 #

# Research cooperation

For purchase and payment details, you may reach us at admin@genomediscovery.org


References:

Web:http://genomediscovery.org or http://newbioideas.com/

Citation: Boominathan, L.,  Atrasentan-based therapy for Cardiac repair and myocardial infarction: Atrasentan, a drug used in the treatment of cancer,  pulmonary hypertension and others, increases Agrin expression, activates Yap and ERK-mediated signaling,  replaces scar tissue with functional cardiomyocytes, and promotes cardiomyocyte regeneration and repair after myocardial infarction, via up-regulation of its target gene, 10/May/2019,  11.48 pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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