Abstract
Aqueous extract of the bark of Terminalia arjuna (TA) is used by a large population in the Indian subcontinent for treating various cardiovascular conditions. Animal experiments have shown its anti-atherogenic, anti-hypertensive, and anti-inflammatory effects. It has several bioactive ingredients with hemodynamic, ROS scavenging, and anti-inflammatory properties. Earlier we have done limited proteomic and transcriptomic analysis to show its efficacy in ameliorating cardiac hypertrophy induced by isoproterenol (ISO) in rats. In the present study we have used high-throughput sequencing of the mRNA from control and treated rat heart to further establish its efficacy. ISO (5 mg/kg/day s.c.) was administered in male adult rats for 14 days to induce cardiac hypertrophy. Standardized aqueous extract TA bark extract was administered orally. Total RNA were isolated from control, ISO, ISO + TA, and TA treated rat hearts and subjected to high throughput sequence analysis. The modulations of the transcript levels were then subjected to bio-informatics analyses using established software. Treatment with ISO downregulated 1,129 genes and upregulated 204 others. Pre-treatment with the TA bark extracts markedly restored that expression pattern with only 97 genes upregulated and 85 genes downregulated. The TA alone group had only 88 upregulated and 26 downregulated genes. The overall profile of expression in ISO + TA and TA alone groups closely matched with the control group. The genes that were modulated included those involved in metabolism, activation of receptors and cell signaling, and cardiovascular and other diseases. Networks associated with those genes included those involved in angiogenesis, extracellular matrix organization, integrin binding, inflammation, drug metabolism, redox metabolism, oxidative phosphorylation, and organization of myofibril. Overlaying of the networks in ISO and ISO_TA group showed that those activated in ISO group were mostly absent in ISO_TA and TA group, suggesting a global effect of the TA extracts. This study for the first time reveals that TA partially or completely restores the gene regulatory network perturbed by ISO treatment in rat heart; signifying its efficacy in checking ISO-induced cardiac hypertrophy.
Highlights
Pathological cardiac hypertrophy (CH) is a major risk factor for heart failure and mortality worldwide
In order to understand the molecular mechanisms of cardioprotection by the TA extracts, we analyzed its effects on the overall signatures of β-adrenergic stimulation in rat heart
To determine molecular basis of the effects of TA on ISO treatment, we performed RNA sequence based differential gene expression analyses. This is a state of the art technology with tremendous potential for revealing multiple molecular cues associated with diseases and their amelioration by the drugs (Doostparast Torshizi and Wang, 2018)
Summary
Pathological cardiac hypertrophy (CH) is a major risk factor for heart failure and mortality worldwide It is characterized by an increase in length and breadth of the cardiac myocytes in association with other physiological/biochemical changes affecting myocardial blood flow, diastolic function, and diminished cardiac output (Shimizu and Minamino, 2016). CH is often associated with an extensive re-programing of gene expression in the heart (Raghow, 2016) Such extensive alterations in cardiac functions is presumably not caused due to the perturbation of a single pathway, but rather a cumulative alteration of many signaling modules including cAMP, PKA, PLC, MAPK, PI3K/Akt, m-TOR etc. While these signaling networks are highly interactive and complex, the categorical goal of pharmacological science is to target the nodal points and the effectors (Walters et al, 2016; Philipson et al, 2017)
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