MicroRNA-410-5p exacerbates high-fat diet-induced cardiac remodeling in mice in an endocrine fashion

Abstract

Metabolic disorders, such as obesity and type 2 diabetes, are associated with an increased risk of cardiomyopathy. To date, microRNA (miRNAs) functions in cardiac remodeling induced by obesity remain to be elucidated. We found that rats fed a high fat diet (HFD) manifested cardiac fibrosis and LV dysfunction. In the heart of rats fed HFD, the phosphorylation levels of Smad 2 and the expression of fibrotic genes, such as connective tissue growth factor, collagen-1α1 (Col1α1), Col3α1, and Col4α1, were up-regulated, which accompanied by an increase in Smad 7 protein levels, but not its mRNA levels. Using miRNA microarray analysis, we showed that the miRNA miR-410-5p inhibited the protein expression of Smad 7, thus increasing the phosphorylation levels of Smad 2. Overexpression of miR-410-5p promoted cardiac fibrosis in rats fed normal diet, whereas inhibition of miR-410-5p by way of miR-410-5p antimiR suppressed cardiac fibrosis in rats fed HFD. Finally, our data revealed that miR-410-5p from the kidney and adipose tissues was probably transferred to heart to induce cardiac fibrosis. Taken together, our study characterizes an endocrine mechanism in which adipose- or kidney-derived circulating miR-410-5p regulates metabolic disorders-mediated cardiac remodeling by activating the TGFβ/Smad signaling in heart.

<p>microRNA Expression Profiles in Myocardium of High-Fat Diet-Induced Obesity Rat</p>

“…5 Zou et al showed that miR-410-5p could exacerbate HFD-induced cardiac fibrosis in mice. 6 As for our research, the results suggested that HFD remarkably induced the expression of miR-141 and miR-144 in rat myocardium, which is consistent with findings in mice, where myocardium remodeling was induced by HFD. 18 For personal use only.…”

“…Although there is mounting evidence that HFD-induced obesity will lead to cardiac dysfunction, hypertrophy, fibrosis, and even heart failure, [4][5][6][7] only few microRNAs have been reported to participate in this process up to now. Kuwabara et al found that knockout of miR-451 in mouse heart could ameliorate HFD-induced cardiac dysfunction and hypertrophy.…”

Clinical efficacies, underlying mechanisms and molecular targets of Chinese medicines for diabetic nephropathy treatment and management

“…Similarly, notoginsenoside R1 was found to protect db / db mice against DN via upregulating NRF2-mediated HO-1 expression 72 . In another study, it was described that administration with ethanol extract of Rhizoma Chuanxiong (25 and 50 mg/kg BW, 3 times per week, 16 weeks) to mice with STZ-induced DN significantly improved urine production, UAER, UACR, and renal morphological damages regarding glomerulosclerosis and fibrosis 145 . In mechanism study, it was found that these effects were mediated by the inhibition of oxidative stress via stimulating the NRF2 signaling pathway and its downstream targets including NQO1 and GCLC 145 .…”

“…Antioxidant response elements (AREs), encoded by the cis -regulatory DNA sequences located in the promoter and enhancer regions, mediates the regulation of NRF2 on downstream molecules. The significance of NRF2/ARE signaling pathway in DN development has been illustrated by accumulative evidence, hence makes NRF2 activation a potential strategy for DN prevention 70 , 72 , 145 .…”

Ischemia/reperfusion injured intestinal epithelial cells cause cortical neuron death by releasing exosomal microRNAs associated with apoptosis, necroptosis, and pyroptosis

“…miR-449a-5p induces apoptosis by regulating Bcl-2 expression 27 . miR-410-3p downregulates the expression of interleukin-10 28 and induces apoptosis 29 . miR-497-5p induces apoptosis via the Bcl-2/Bax-caspase-9-caspase-3 pathway 30 .…”