Polypill for cardioprotection: Combinatorial therapy for postnatal Cardiomyocyte proliferation, repair and regeneration:  A four-component Polypill consisting of Hydrochlorothiazide (12·5 mg), Aspirin (81 mg), Atorvastatin (20 mg), and Enalapril (5 mg) or Valsartan (40 mg) [Polypill-HAAE/HAAV]  decreases tumor suppressor MiR-128 and cyclin-dependent kinase inhibitor p27 expression, increases SUZ12 expression, increases Cyclin E and CDK2 expression, promotes proliferation/re-entry of postnatal/adult cardiomyocytes, attenuates fibrosis, ameliorates cardiac dysfunction, and promotes heart repair in response to myocardial infarction, via up-regulation of its target gene, 13/September/2019, 7.43 pm

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Introduction: What they say:

A recent study from Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Key Laboratory of Molecular Target and Clinical Pharmacology, School of Pharmaceutical Sciences & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China; and Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA shows that “Loss of microRNA-128 promotes cardiomyocyte proliferation and heart regeneration.” This study was published, in the 16 Feb 2018 issue of Nature communications (one of the best journals in science with an impact factor of 16+), by Prof Wang Y, Huang W, and others.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that:  Polypill for cardioprotection: Combinatorial therapy for postnatal Cardiomyocyte proliferation, repair and regeneration:  A four-component Polypill consisting of Hydrochlorothiazide (12·5 mg), Aspirin (81 mg), Atorvastatin (20 mg), and Enalapril (5 mg) or Valsartan (40 mg) [Polypill-HAAE/HAAV]  decreases tumor suppressor MiR-128 and cyclin-dependent kinase inhibitor p27 expression, increases SUZ12 expression, increases Cyclin E and CDK2 expression, promotes proliferation/re-entry of postnatal/adult cardiomyocytes, attenuates fibrosis, ameliorates cardiac dysfunction, and promotes heart repair in response to myocardial infarction, via up-regulation of its target gene


From the 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; (5) the death due to cardiovascular disease is higher in low-to-middle income countries compared to developed countries; (6) the global economic cost spent in the treatment of cardiovascular disease in 2011 was little more than 10 billion US dollars; (7) 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 (iii) a side-effect-free Natural product-based drug.


What is known?

Prof Wang’s research team has shown recently that: (1) miRNA-128 is upregulated in terminally differentiated cardiomyocytes (CMs); (2) Overexpression of MiR-128 in cardiomyocytes inhibits cardiomyocyte proliferation and function; (3) Deletion of miR-128 in postnatal cardiomyocytes increase proliferation by increasing the expression of DNA modifying protein SUZ12; (4) Increased expression of Suz12 inhibits the expression of cyclin-dependent kinase inhibitor p27; (5) Down-regulation of p27 results in increased expression of the positive regulators of cell cycle, such as Cyclin E and CDK2; and (6) Deletion of MiR-128: (a) drives adult cardiomyocytes to re-enter into cell cycle; (b) attenuates fibrosis; and (c) suppresses cardiac dysfunction in response to myocardial infarction, suggesting that inhibition of miR-128 expression may promote cardiomyocyte proliferation and heart regeneration.


From research findings to therapeutic opportunity:

A study from the Digestive Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran; Digestive Oncology Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran; Liver and Pancreaticobiliary Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran and others shows that “Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial. This study was published, in the 24 August 2019 issue of of the prestigious journal Lancet (Impact factor: 53+)by  Prof. Malekzadeh R, M.D., Roshandel G Ph.D., and others. This study suggests that  patients who consumed a four-component Polypill consisting of Hydrochlorothiazide (12·5 mg), Aspirin (81 mg), Atorvastatin (20 mg), and Enalapril (5 mg)  or Valsartan (40 mg)  Polypill-HAEE/V are associated with reduced risk of  major cardiovascular events.  However, the precise mechanism of action the four-component polypill remains unclear. 

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

Polypill-HAEE/V, by increasing the expression of its target genes, it may decrease the expression of tumor suppressor gene miRNA-128 (that impedes postnatal cardiomyocyte proliferation) (fig.1). Thereby, it could: (1) increase the expression of Suz12;(2) decrease the expression of CDK inhibitor p27; (3) increase the expression of gene products that promote cardiac proliferation, including Cyclin E and CDK2;(4) increase the expression of miRNAs that promote cardiac regeneration;(5) increase post-natal cardiomyocyte proliferation; (6) suppress fibrosis; (7) promote cardiomyocyte survival/regeneration; (8) promote cardiomyocyte repair, and recovery after myocardial infarction; (9) attenuate cardiac ageing; and (10) extend lifespan (fig 1). Thus, by treating cardiac patients withPolypill-HAEE/V or its analogs or equivalents that share their mechanism of action, one may preserve myocardial function after myocardial infarction; and prevent aging-associated (or, stress-associated) decline in cardiac function.

In conclusion, this study suggests, for the first time, with detailed mechanistic insights, that pharmacological formulations encompassing a four-component Polypill consisting of Hydrochlorothiazide (12·5 mg), Aspirin (81 mg), Atorvastatin (20 mg), and Enalapril (5 mg) or Valsartan (40 mg) [Polypill-HAAE/HAAV]   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).

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

Thus, those who are above 55 years of age, by taking Polypill-HAAE/HAAV, 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-HAAE/HAAV may protect against cardiac dysfunction and heart failure in the long-term (figs. 4-5).  

Figure 1. A four-component Polypill consisting of Hydrochlorothiazide (12·5 mg), Aspirin (81 mg), Atorvastatin (20 mg), and Enalapril (5 mg) or Valsartan (40 mg) [Polypill-HAAE/HAAV]  functions as a cardioprotective agent. Mechanistic insights into how Polypill-HAAE/HAAV decreases the expression of MiR-128, and CDKI p27,  increases the expression of Cyclin E and CDK2, and regulates the expression of other genes that promote cardiac repair and regeneration.

Figure 2. Polypill-HAAE/HAAV may function as a cardioprotective agent through induction of  MiR-128, CDKI p27; and down-regulation of Cyclin E and CDK2

Figure 2. The chemical structure of the constituents of  Polypill-HAAE [Hydrochlorothiazide (12·5 mg), Aspirin (81 mg), Atorvastatin (20 mg), and Enalapril (5 mg)].  Polypill-HAAE functions as a cardioprotective agent through induction of  MiR-128, CDKI p27; and down-regulation of Cyclin E and CDK2

Figure 3. The chemical structure of the constituents of  Polypill-HAAV  [Hydrochlorothiazide (12·5 mg), Aspirin (81 mg), Atorvastatin (20 mg), and  Valsartan (40 mg)]. It functions as a cardioprotective agent through down regulation of  MiR-128, CDKI p27; and up-regulation of Cyclin E and CDK2

Figure 4. While it has been shown earlier that genetic ablation of miR-128 promotes cardiac regeneration, enhances cardiac contractility, and functional recovery after myocardial infarction, the study presented here suggests that Polypill-HAAE/HAAV functions as a cardioprotective agent through down regulation of MiR-128, CDKI p27; and up-regulation of Cyclin E and CDK2. And, thereby, it makes those who take Polypill-HAEE less susceptible to cardiac dysfunction.

Figure 5. While it has been shown earlier that genetic ablation of miR-128 promotes cardiac regeneration, enhances cardiac contractility, and functional recovery after myocardial infarction, the study presented here suggests that Polypill-HAAE/HAAV functions as a cardioprotective agent through down regulation of MiR-128, CDKI p27; and up-regulation of Cyclin E and CDK2. And, thereby, it makes those who take Polypill-HAEE/V less susceptible to cardiac dysfunction.

 


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-HAAE/HAAV decrease the expression of MiR-128 and p27 and promote postnatal cardiomyocyte proliferation, repair and regeneration?

Amount: $ 1, 500 #

# Research cooperation

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


References:  Polypill can protect against cardiac dysfunction.

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

Citation: Boominathan, L., Polypill for cardioprotection: Combinatorial therapy for postnatal Cardiomyocyte proliferation, repair and regeneration:  A four-component Polypill consisting of Hydrochlorothiazide (12·5 mg), Aspirin (81 mg), Atorvastatin (20 mg), and Enalapril (5 mg) or Valsartan (40 mg) [Polypill-HAAE/HAAV]  decreases tumor suppressor MiR-128 and cyclin-dependent kinase inhibitor p27 expression, increases SUZ12 expression, increases Cyclin E and CDK2 expression, promotes proliferation/re-entry of postnatal/adult cardiomyocytes, attenuates fibrosis, ameliorates cardiac dysfunction, and promotes heart repair in response to myocardial infarction, via up-regulation of its target gene, 13/September/2019, 7.43 pm, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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