Growth differentiation factor 11 attenuates cardiac ischemia reperfusion injury via enhancing mitochondrial biogenesis and telomerase activity

Abstract

It has been reported that growth differentiation factor 11 (GDF11) protects against myocardial ischemia/reperfusion (IR) injury, but the underlying mechanisms have not been fully clarified. Considering that GDF11 plays a role in the aging/rejuvenation process and that aging is associated with telomere shortening and cardiac dysfunction, we hypothesized that GDF11 might protect against IR injury by activating telomerase. Human plasma GDF11 levels were significantly lower in acute coronary syndrome patients than in chronic coronary syndrome patients. IR mice with myocardial overexpression GDF11 (oe-GDF11) exhibited a significantly smaller myocardial infarct size, less cardiac remodeling and dysfunction, fewer apoptotic cardiomyocytes, higher telomerase activity, longer telomeres, and higher ATP generation than IR mice treated with an adenovirus carrying a negative control plasmid. Furthermore, mitochondrial biogenesis-related proteins and some antiapoptotic proteins were significantly upregulated by oe-GDF11. These cardioprotective effects of oe-GDF11 were significantly antagonized by BIBR1532, a specific telomerase inhibitor. Similar effects of oe-GDF11 on apoptosis and mitochondrial energy biogenesis were observed in cultured neonatal rat cardiomyocytes, whereas GDF11 silencing elicited the opposite effects to oe-GDF11 in mice. We concluded that telomerase activation by GDF11 contributes to the alleviation of myocardial IR injury through enhancing mitochondrial biogenesis and suppressing cardiomyocyte apoptosis.

Circulating GDF11 exacerbates myocardial injury in mice and associates with increased infarct size in humans

“…Next, we sought to study myocardial expression levels of both Gdf11 and Mstn in mice undergoing myocardial I/R injury and their respective controls. In line with previous reports in 8–10-week-old mice, 59 , 60 a marked decline in Gdf11 but an increase in Mstn expression was observed upon I/R ( Figure 1 B ). Of note, Magga et al 59 have shown that these changes are accentuated early after I/R and are more prominent in the infarcted rather than the peri-infarcted area, suggesting that changes in endogenous Gdf11 expression levels are predominantly induced by the ischaemic insult, and as such interfering with Gdf11 signalling may have therapeutic effects.…”

“…Mstn and Gdf11 share many functional properties for muscle mass control in mice, 75 but the contrasting myocardial expression pattern during ageing and upon I/R injury ( Figure 1 B ) 59 , 60 coupled with marked differences in their predictive utility for final infarct size in human patients ( Figure 5 C ) strongly suggests that GDF11 and MSTN play distinct roles during I/R injury. In fact, both aptamer- and antibody-based detection methods commonly employed in the past were found to be non-specific for GDF11 (and thus to cross-react with MSTN): indeed, in contrast to the initial paradigm, 27 , 28 various studies have reported variable or no significant age-related change in GDF11 protein levels in humans.…”

Insights into bone morphogenetic proteins in cardiovascular diseases

“…BMP-11 overexpression with an adenovirus was reported to alleviate cardiac ischemia-reperfusion injury by enhancing mitochondrial biogenesis and telomerase activity in rats (Chen et al, 2021). These researchers also found that BMP-11 depletion resulted in the opposite effect in mice (Chen et al, 2021).…”

“…BMP-11 overexpression with an adenovirus was reported to alleviate cardiac ischemia-reperfusion injury by enhancing mitochondrial biogenesis and telomerase activity in rats (Chen et al, 2021). These researchers also found that BMP-11 depletion resulted in the opposite effect in mice (Chen et al, 2021). Furthermore, BMP-11 overexpression reduced cardiomyocyte apoptosis and improved cardiac function, thus enhancing myocardial regeneration after ischemia-reperfusion injury in aging mice (Du et al, 2017).…”

Potential Therapies to Protect the Aging Heart Against Ischemia/Reperfusion Injury

“…By the same token, overexpression of telomerase can confer cardioprotection in mice hearts (60). Furthermore, overexpression of growth differentiation factor 11 (GDF11) in mice subjected to in vivo I/R injury showed a reduced infarct size, activation of telomerase, longer telomeres and increased mitochondrial biogenesis (61). In a clinical context, Gupta et al have published a pilot study that proposes telomere length as a screening tool for patients with acute myocardial infarction (62).…”