Cardiovascular Polypill-LAAH attenuates pathogenesis-associated with Myocardial infarction and protects against myocardial dysfunction:   A four-component Polypill-LAAH consisting of Losartan(25 mg), Amlodipine (2.5 mg), Atorvastatin (10 mg), and Hydrochlorothiazide (12·5 mg)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, 1/October/2019, 12.04 pm

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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: Cardiovascular Polypill-LAAH attenuates pathogenesis-associated with Myocardial infarction and protects against myocardial dysfunction:   A four-component Polypill-LAAH consisting of Losartan(25 mg), Amlodipine (2.5 mg), Atorvastatin (10 mg), and Hydrochlorothiazide (12·5 mg)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 the Vanderbilt Translational and Clinical Cardiovascular Research Center, the Division of Cardiovascular Medicine, the Division of Epidemiology, Department of Medicine, and Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Vanderbilt University, Nashville; and Franklin Primary Health Center, USA and others shows that “Polypill for Cardiovascular Disease Prevention in an Underserved Population.” This study was published, in the 19 September 2019 issue of of the prestigious journal  N Engl J Med (Impact factor: 70+)by  Prof. Thomas J. Wang, M.D., Munoz D M.D., and others. This study suggests that those  patients who consumed a four-component Polypill-LAAH consisting of Losartan (25 mg), Amlodipine (2.5 mg), Atorvastatin (10 mg), and Hydrochlorothiazide (12·5 mg)  had  greater reductions in systolic blood pressure and Low-density lipoprotein (LDL) levels.  However, the precise mechanism of action of the four-component polypill remains largely unclear. 

The study presented here substantiates and supports the aforementioned study’s’ claim, and of others, by providing detailed mechanistic insights into how Polypill-LAAH attenuates and thereby protects against hypertension and myocardial dysfunction, including cardiac hypertrophy, fibrosis of the myocardium, cardiac ageing and myocardial infarction.

This study provides, for the first time, mechanistic insights into how Polypill-LAAH may aid in lowering blood pressure, decreasing LDL levels, attenuating parthenogenesis associated with myocardial infarction, promoting cardiac repair after myocardial infarction. 

This study suggests a combinatorial therapy for attenuating pathogenesis-associated with Myocardial infarction. Polypill-LAAH, by regulating the expression of its target genes, it may decrease the expression of IRF3, GRK2 and GM-CSF (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 Polypill-LAAH or its individual constituent’s analogs or its mechanistic/functional equivalents, either alone or in combination with other drugs,” can be used to heal/repair damaged cardiac tissue after myocardial infarction. Together, Polypill-LAAHbased 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 Polypill-LAAH or its individual constituent’s analogs 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 pharmacological formulations encompassing a four-component Polypill consisting of Losartan (25 mg),  Amlodipine (2.5 mg), Atorvastatin (10 mg), and Hydrochlorothiazide (12·5 mg) 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).

Figure 1. Polypill-LAAH  functions as a Cardioprotective agent. Mechanistic insights into how a four-component Polypill consisting of Losartan (25 mg),  Amlodipine (2.5 mg), Atorvastatin (10 mg), and Hydrochlorothiazide (12·5 mg) [Polypill-LAAHprotect against cardiac dysfunction and hypertension. It protects against myocardial infarction and hypertension through down regulation of GRK2, and-GM-CSF and other genes.

Figure 2. Polypill-LAAH protect 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. The chemical structure of constituents of Polypill-LAAH.

Figure 4. 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 Polypill-LAAH 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. While it had been shown recently that Polypill-LAAH decreases systotolic blood pressure and LDL levels, the study presented here suggests that Polypill-LAAH may attenuate IRF3, GRK2, and GM-CSF expression, suppress pathogenesis-associated with myocardial infarction, and increase the expression of genes that promote cardiomyocyte survival and repair.

Together, the study presented here, provides, for the first time, plausible explanation and mechanistic and functional insights into how Polypill-LAAH may attenuate the risk of cardiac dysfunction.

Thus, those who are above 55 years of age, by taking Polypill-LAAH, 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 Polypill-LAAH 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 Polypill-LAAH decrease the expression of IRF3, GRK2 and IRF3?

Amount: $1, 500 #

# Research cooperation

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

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References:

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

Citation: Boominathan, L., Cardiovascular Polypill-LAAH attenuates pathogenesis-associated with Myocardial infarction and protects against myocardial dysfunction:   A four-component Polypill-LAAH consisting of Losartan(25 mg), Amlodipine (2.5 mg), Atorvastatin (10 mg), and Hydrochlorothiazide (12·5 mg)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, 1/October/2019, 12.04 pm, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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