Introduction: What they say:
A recent study from Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA; and Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA shows that “IRF3 and type I interferons fuel a fatal response to myocardial infarction.” This study was published, in the 6 November 2017 issue of Journal Nature Medicine (One of the best journals in Bio-Medicine with an impact factor of 29.886), by Prof Ralph Weissleder, Kevin R King and others.
What we say:
On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Molecular mechanistic insights into how antiplatelet drug Prasugrel attenuates pathogenesis-associated with Myocardial infarction and protects against myocardial dysfunction: Prasugrel (Trade name: Effient, Efient), a drug used to prevent blood clots, decreases IRF3, GM-CSF (Granulocyte-macrophage colony-stimulating factor) and GRK2(G protein-coupled receptor kinase) expression, inhibits undue leukocyte activation and invasion, suppresses recruitment of inflammatory cells, inhibits ventricular dilation, and promotes heart repair and survival, via up regulation of its target genes
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 from 2030 onwards, 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.
What is known?
It is known for years that myocardial infarction results in activation of inflammatory mediators and excessive recruitment of leukocytes near the damaged myocardium. However, the mechanistic basis of which is far from clear.
Prof Ralph Weissleder FK’s research team has shown recently that: (1) mice null for IRF3 and IFNAR have improved survival after myocardial infarction; (2) inhibition of IRF3 signalling: a) decreases the expression of cardiac inflammatory mediators; b) prevents inflammatory cell infiltration of the myocardium; c) reduces ventricular enlargement; and d) ameliorates cardiac function; and (3) treating mice with IFNAR-neutralizing antibody alter myocardial infarction: a) attenuates interferon response; b) improves left ventricular dysfunction; and (c) promotes survival, suggesting that inhibition of IRF3 or IFNAR expression may: (1) attenuate pathogenesis after myocardial infarction; (2) aid post-myocardial infarction protection; and (3) stall myocardial infarction from progressing to heart failure.
From Research Findings to Therapeutic Opportunity:
A study from the Department of Cardiology, Deutsches Herzzentrum, Lazarettstr. 36, 80636 Munich, Germany and others shows the effect of “Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes.” This study was published, in the 17 October 2019 issue of of the prestigious journal N Engl J Med (Impact factor: 70+), by Prof. Stefanie Schüpke, M.D., and others. This study suggests that: (1) when treated with Ticagrelor, the primary end-point occurred in 184 of 2012 patients, while with Prasugrel 137 of 2006; (2) the incidence of death, myocardial infarction, or stroke was significantly low when treated with Prasugrel compared with Ticagrelor. However, (1) the precise mechanism of action of Prasugrel remains largely unclear; and (2) why Prasugrel is better than Ticagrelor in protecting against cardiovascular dysfunction and stroke.
The study presented here substantiates and supports the aforementioned study’s’ claim, and of others, by providing detailed mechanistic insights into how Prasugrel attenuates myocardial dysfunction, including cardiac hypertrophy, fibrosis of the myocardium, cardiac ageing, and myocardial infarction.
Furthermore, this study provides, for the first time, mechanistic insights into how Prasugrel may aid in attenuating parthenogenesis associated with myocardial infarction, and promoting cardiac repair after myocardial infarction.
Prasugrel, by regulating the expression of its target genes, it may decrease the expression of IRF3(Interferon regulatory factor 3), GRK2 (G Protein-Coupled Receptor Kinase 2) and GM-CSF (Granulocyte-macrophage colony-stimulating factor) (fig.1). Thereby, it may: (i) inhibit the expression of inflammatory mediators; (ii) stall inflammatory cell infiltration; (iii) inhibit ventricular dilation; (iv) improve cardiac function and survival; and (v) inhibit inflammatory reaction post-MI. Thus, a pharmacological mixture encompassing “Prasugrel or its analogs/mechanistic/functional equivalents, either alone or in combination with other drugs,” can be used to heal/repair damaged cardiac tissue after myocardial infarction. Together, Prasugrel–based therapy may be used to heal/repair damaged cardiac tissue after myocardial infarction or protect from myocardial infarction (Fig.1).
Thus, by treating myocardial patients with Prasugrel or functional or mechanistic equivalents of its analogs, cardiologists may preserve myocardial function after myocardial infarction; and prevent ageing-associated (or, stress-associated) decline in cardiac function (fig. 2).
In conclusion, this study suggests, for the first time, with detailed mechanistic insights, that (a) pharmacological formulations encompassing “Prasugrel or its analogs or functional equivalents that share their mechanism of action, either alone or in combination with any of the known compounds that improve myocardial function,” may be used to heal damaged cardiac tissue, and repair and regenerate new cardiomyocytes after myocardial infarction (fig.2); and (b) why Prasugrel is a better drug in treating myocardial dysfunction compared with Ticagrelor.
Figure 1. Mechanistic insights into how Prasugrel protects against cardiac dysfunction. It protects against myocardial dysfunction through down regulation of IRF3, GRK2, and-GM-CSF and other genes.
Figure 2. Prasugrel protects against pathogenesis associated with myocardial infarction through down regulation of GM-CSF, GRK2, IRF3 and up regulation of genes that promote cardiomyocyte survival and proliferation.
Figure 3. While it had been shown that genetic ablation or pharmacological intervention of IRF3, GM-CSF and GRK2, attenuates pathogenesis-associated with myocardial infarction, the study presented here suggests that Prasugrel may attenuate IRF3, GRK2, and GM-CSF expression, suppress pathogenesis-associated with myocardial infarction, and increase the expression of genes that promote cardiomyocyte survival.
Figure 5. Although it is shown/published today (Oct 17, 2019) that Prasugrel protects better against acute coronary syndrome than Ticagrelor, its precise mechanism of action remains far from clear. The study presented here suggests that Prasugrel may: (1) attenuate IRF3, GRK2, and GM-CSF expression; (2) suppress pathogenesis-associated with myocardial infarction; and (3) increase the expression of genes that promote cardiomyocyte survival and repair. And, thereby, protects against acute coronary syndromes.
Together, the study presented here, provides, for the first time, plausible explanation and mechanistic and functional insights into how Prasugrel may attenuate the risk of cardiac dysfunction.
Thus, those who are above 55 years of age, by taking Prasugrel, they may prevent ageing-associated (or, stress-associated) decline in cardiac function and cardiac dysfunction (fig. 2).
Finally, this study provides, for the first time, mechanistic and functional insights into how Prasugrel may protect against cardiac dysfunction and heart failure in the long-term (figs. 4-5).
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 does Prasugrel decrease the expression of IRF3, GRK2 and IRF3?
Amount: $1, 500 #
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References:
Web:http://genomediscovery.org or http://newbioideas.com/
Citation: Boominathan, L., Molecular mechanistic insights into how Prasugrel attenuates pathogenesis-associated with Myocardial infarction and protects against myocardial dysfunction: Prasugrel (Trade name: Effient, Efient), a drug used to prevent blood clots, decreases IRF3, GM-CSF (Granulocyte-macrophage colony-stimulating factor) and GRK2(G protein-coupled receptor kinase) expression, inhibits undue leukocyte activation and invasion, suppresses recruitment of inflammatory cells, inhibits ventricular dilation, and promotes heart repair and survival, via up regulation of its target genes, 17/October/2019, 11.29 pm, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org
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