Cordycepin ameliorates cardiac hypertrophy via activating the AMPKα pathway

Abstract

Increase of myocardial oxidative stress is closely related to the occurrence and development of cardiac hypertrophy. Cordycepin, also known as 3'‐deoxyadenosine, is a natural bioactive substance extracted from Cordyceps militaris (which is widely cultivated for commercial use in functional foods and medicine). Since cordycepin suppresses oxidative stress both in vitro and in vivo, we hypothesized that cordycepin would inhibit cardiac hypertrophy by blocking oxidative stress‐dependent related signalling. In our study, a mouse model of cardiac hypertrophy was induced by aortic banding (AB) surgery. Mice were intraperitoneally injected with cordycepin (20 mg/kg/d) or the same volume of vehicle 3 days after‐surgery for 4 weeks. Our data demonstrated that cordycepin prevented cardiac hypertrophy induced by AB, as assessed by haemodynamic parameters analysis and echocardiographic, histological and molecular analyses. Oxidative stress was estimated by detecting superoxide generation, superoxide dismutase (SOD) activity and malondialdehyde levels, and by detecting the protein levels of gp91 phox and SOD. Mechanistically, we found that cordycepin activated activated protein kinase α (AMPKα) signalling and attenuated oxidative stress both in vivo in cordycepin‐treated mice and in vitro in cordycepin treated cardiomyocytes. Taken together, the results suggest that cordycepin protects against post‐AB cardiac hypertrophy through activation of the AMPKα pathway, which subsequently attenuates oxidative stress.

A Systematic Review of the Biological Effects of Cordycepin

“…Five of these met the eligibility criteria (see the Methods section). The outcomes were activation of AMPK indicated by increasing phosphorylation at Thr 172 (three articles) and also inhibiting mTOR indicated by reduced the phosphorylation at Ser 2448 (two articles), confirming the effects observed in tissue culture [35,142,164,183,184]. For details see Table 2.…”

“…We noted 45 papers claiming that the cytotoxic effect of cordycepin at bioactive concentrations was low. We noted the highest concentration which promoted cell survival or did not cause statistically significant cell death in these papers and determined the median and the range [ 28 , 29 , 30 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 69 , 70 , 80 , 95 , 98 , 102 , 105 , 106 , 117 , 142 , 145 , 164 , 184 , 240 , 270 , 301 , 315 , 317 , 326 , 327 , 328 , 329 , 330 , 331 , 332 , 333 , 334 , 335 , 336 ].…”

“…For example, in papers studying the effect of cordycepin on osteoarthritic animal models where pain was also measured, the study was categorised under bone disorders. The range of cordycepin dose administered to the animal was examined in 131 papers, in which the cordycepin dose could be calculated as mg/kg [ 11 , 18 , 23 , 24 , 28 , 37 , 38 , 42 , 64 , 66 , 76 , 79 , 80 , 97 , 107 , 108 , 119 , 120 , 121 , 122 , 126 , 130 , 134 , 142 , 143 , 145 , 150 , 164 , 183 , 184 , 185 , 186 , 187 , 188 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 202 , 204 , 205 , 206 , 207 ...…”

“…Concerning the cardiovascular system, 15 articles were found for a variety of animal models. Cordycepin was reported to have beneficial effects for cardiac hypertrophy [184], ischemia [122,183,[204][205][206], dyslipidaemia [37,164,207,208] and other heart disease models [76,120,[209][210][211]. Categories which had only one entry were excluded, as described in the Methods section.…”

Cordycepin Decreases Ischemia/Reperfusion Injury in Diabetic Hearts via Upregulating AMPK/Mfn2-dependent Mitochondrial Fusion

“…Numerous studies have found that AMPK activation appears to have a protective effect on cardiomyocytes under MI/R by decreasing apoptosis, improving post-ischemic recovery, and reducing myocardial infarction (MI) ( Wu and Zou, 2020 ). Interestingly, cordycepin has been reported as a pro-drug that activates AMPK by being converted into the AMP analog cordycepin monophosphate ( Wu et al, 2014 ; Wang et al, 2019 ; Hawley et al, 2020 ). Moreover, recent studies have demonstrated that AMPK regulates mitochondrial fusion and mitophagy to sustain mitochondrial homeostasis under stress conditions ( Toyama et al, 2016 ; Zhang et al, 2019 ), indicating the key role of AMPK in mitochondrial dynamics.…”