Bone morphogenetic protein 10 alleviates doxorubicin-induced cardiac injury via signal transducer and activator of transcription 3 signaling pathway

Abstract

Doxorubicin (DOX) has limited antitumor applications owing to its association with life-threatening cardiac injury. Oxidative damage and cardiac apoptosis are crucial in DOX-induced cardiac injury. Bone morphogenetic protein 10 (BMP10) is predominantly distributed in the heart and acts as a cardioprotective factor that preserves cardiac function. However, the role of BMP10 in DOX-induced cardiac injury has not yet been explored. The current study aimed to examine the function and mechanism of action of BMP10 in DOX-induced cardiac injury. An adeno-associated viral system was used for the overexpression or silencing of cardiac-specific BMP10, and subsequently, a single dose of DOX was intraperitoneally injected to induce cardiac injury. Results showed that DOX exposure decreased BMP10 expression in the heart. Cardiac-specific overexpression of BMP10 alleviated the oxidative stress and apoptosis and improved cardiac function. Conversely, cardiac-specific silencing of BMP10 aggravated the redox disorder and apoptosis and worsened the cardiac dysfunction caused by DOX. Exogenous BMP10 supplementation amelioratesd the DOX-induced cardiac contractile dysfunction. Mechanistically, we found that phosphorylation of signal transducer and activator of transcription 3 (STAT3) is reduced in DOX-induced cardiotoxicity, and, BMP10 activated impaired STAT3 via a non-canonical pathway. BMP10 lost its cardioprotective function in cardiomyocyte-specific STAT3 knockout (STAT3-cKO) mice. Based on our findings, we suggested that BMP10 is a potential therapeutic agent against DOX-induced cardiac injury and that the cardioprotective effects of BMP10 are dependent on the activation of STAT3.

Insights into bone morphogenetic proteins in cardiovascular diseases

“…Previously, BMP-2 was reported to alleviate DOX-induced cardiomyocyte injury in vitro (Izumi et al, 2006). Recently, Peng et al reported that DOX treatment decreased BMP-10 expression in mouse hearts and that cardiac-specific BMP-10 inhibition aggravated oxidative stress and apoptosis and worsened cardiac function, whereas cardiac-specific BMP-10 overexpression and exogenous BMP-10 supplementation ameliorated DOX-induced cardiac dysfunction by activating STAT3 signaling (An et al, 2022).…”

Leucine zipper protein 1 prevents doxorubicin-induced cardiotoxicity in mice

“…To establish acute cardiotoxicity, male mice with 8-10-week-old were injected with DOX (15 mg/kg, i.p.) once, and then sacrificed by cervical dislocation 8 days post-DOX injury [ 22 ]. To clarify the role of AMPK in LUZP1-mediated protections against DOX-induced cardiotoxicity, LUZP1 cTG mice were mated with Ampkα2 knockout (KO) mice to generate cardiac-specific Luzp1 transgenic mice with Ampkα2 deficiency, and global Ampkα2 KO mice has been used previously [ 14 ].…”

“…To clarify the role of AMPK in LUZP1-mediated protections against DOX-induced cardiotoxicity, LUZP1 cTG mice were mated with Ampkα2 knockout (KO) mice to generate cardiac-specific Luzp1 transgenic mice with Ampkα2 deficiency, and global Ampkα2 KO mice has been used previously [ 14 ]. To specifically silence PPP1CA/B in the myocardium, LUZP1 cKO mice were injected from tail vein with AAV9 (1 × 10 11 VG particles/mouse) carrying pan PP1 shRNA (sh PP1 , #sc-43533; Santa Cruz, Dallas, Texas, USA) under a cTnT promoter 4 weeks pre-DOX injury [ [22] , [23] , [24] ]. To investigate whether LUZP1 overexpression also conferred cardioprotective effects on DOX-induced chronic injury, LUZP1 cTG mice or the non-transgenic (NTG) controls were weekly injected with 5 mg/kg DOX (i.p.)…”

“…Finally, the OD value was recorded at 450/655 nm. The levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), CAT activity, total SOD activity and caspase-3 activity were detected following our previous studies [ 22 , 25 , 31 ].…”

Bone morphogenetic protein 10, a rising star in the field of diabetes and cardiovascular disease

“…Although DOX exposure decreased the initial level of BMP10 in the heart, exogenous supplementation may ameliorate DOX‐induced systolic dysfunction. DOX cardiotoxicity decreased phosphorylation of signal transducer and activator of transcription 3 (STAT3), and exogenous BMP10 reversed the defective STAT3 via a noncanonical pathway 38 . Hence, it is evident that BMP10 has the capacity to elicit cardiomyocyte value‐added and thereby counteract cardiac damage, both for cell death due to myocardial ischemia and cardiac injury induced by drugs, and that this capacity might be achieved via the STAT3 pathway.…”