Introduction: What they say:
A recent study, from Department of Medicine, Division of Cardiology, Dept of Cell Biology, and Department of Molecular Genetics, Duke University Medical Center, Durham, North Carolina, USA, shows that “Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of ß-adrenergic receptor signaling.” This study was published, in the 7 September 2017 issue of JCI (Journal of Clinical Investigation) Insight, by Prof Shenoy, Jean-Charles PY and others.
What we say:
On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Vitamin-based therapy for improving cardiac contractility and attenuating pathogenesis-associated with Myocardial infarction: Phytonadione/Mephyton/VitaminK1 decreases GRK2 (G Protein-Coupled Receptor Kinase 2) and GM-CSF (Granulocyte-macrophage colony-stimulating factor) expression, increases cardiac contractility, inhibits undue leucocyte activation and invasion, suppresses recruitment of inflammatory cells, inhibits left ventricular rupture, promotes heart healing and inhibits glucose intolerance, 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.
What is known?
Earlier studies showed that MDM2, a RING domain-containing E3 ubiquitin ligase and widely known negative regulator of tumor suppressor p53, ubiquitinates G protein-coupled receptor kinase 2 (GRK2) and ß-arrestin2. And thereby, control ß-adrenergic receptor (ßAR) signaling and endocytosis.
Prof Shenoy’s research team has shown recently that: (1) MDM2 regulates cardiac ß1AR signaling; (2) in response to isoproterenol treatment, cAMP levels are increased in left ventricles of Wild-type mice, but not in Mdm2/p53-KO mice; (3) isoproterenol treatment also results in impairment of calcium signalling in left ventricles of Wild-type mice, but not in Mdm2/p53-KO mice; (4) GRK2 levels are increased in Mdm2/p53-KO mice compared to Wild-type mice; (5) GRK2 polyubiquitination is impaired in Mdm2/p53-KO hearts; (6) deleting MDM2 in Cardiomyocytes results in a) increased expression of GRK2; b) impaired cardiac function; c) high mortality; and d) non-responsiveness to ßAR; and (7) induction of MDM2 gene in Mdm2/p53-KO mice rescues ß1AR-induced cardiac contractility, suggesting that either increased expression of MDM2 or attenuation of GRK2 expression in cardiomyocytes may enhance cardiac contractility and function by attenuating GRK2-mediated desensitization of ßAR signalling.
From Research Findings to Therapeutic Opportunity:
This study suggests, for the first time, that Vitamin K1 may promote cardiac contractility and attenuate pathogenesis-associated with Myocardial infarction.
Phytonadione/Mephyton/VitaminK1, by increasing the expression of its target genes, it may decrease the expression of GRK2 and GM-CSF (fig.1). Thereby, it may: (i) sensitize ßAR signalling; (ii) increase cardiac contractility; (iii) increase sympatholytic activity; (iv) improve cardiac function; (v) stall recruitment of inflammatory and proteolytic cells;(vi) inhibit accumulation of excessive amount of neutrophils and monocytes near the damaged myocardium; (vii) inhibit left ventricular rupture and remodelling; (viii) suppress leukocyte supply chain; (ix) control excessive inflammatory reaction; (x) inhibit cardiac hypertrophy; (xi) inhibit cardiac ageing; (xii) increase glucose tolerance; (xiii) augment insulin sensitivity; (xiv) promote vascular endothelial function; (xv) attenuate Hypertension; (xvi) promote Weight loss and lean mass; (xvii) extend Lifespan (figs. 1-3).
Together, this study suggests that pharmacological formulations encompassing “Phytonadione/Mephyton/VitaminK1 or its analogs, either alone or in combination with other drugs,” may be used to increase cardiac contractility and heal damaged cardiac tissue after myocardial infarction (fig. 1).
Details of the research findings:
Idea Proposed/Formulated (with experimental evidence) by:
Dr L Boominathan Ph.D.
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Undisclosed mechanistic information: How Vitamin K1 decreases the expression of GRK2 and GM-CSF, inhibits inflammatory leukocyte recruitment, and attenuates the pathogenesis associated with myocardial infarction
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Citation: Boominathan, L., Vitamin-based therapy for improving cardiac contractility and attenuating pathogenesis-associated with Myocardial infarction: Phytonadione/Mephyton/VitaminK1 decreases GRK2 (G Protein-Coupled Receptor Kinase 2) and GM-CSF (Granulocyte-macrophage colony-stimulating factor) expression, increases cardiac contractility, inhibits undue leucocyte activation and invasion, suppresses recruitment of inflammatory cells, inhibits left ventricular rupture, promotes heart healing and inhibits glucose intolerance, via up regulation of its target gene, 4/January/2017, 6.17 am, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org
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