pAKT pathway activation has cardioprotective effects…
Chemotherapy and anti-cancer drugs are designed to cure cancer. With the increasing success of cancer therapies for treating cancer, life-saving treatments can sometimes cause side-effects in the heart and vascular system called cardiotoxicity. Cardiotoxicity can develop during cancer treatment, or it can occur within days, months, or even years after cancer treatment, once patients are cancer-free. Heart damage caused by chemotherapy-induced cardiotoxicity can reduce quality of life and increase the risk of death from cardiac-related causes.
Anthracyclines, such as doxorubicin, are perhaps the most notorious offenders regarding chemotherapeutic cardiotoxicity documented so far. Used to treat breast cancer, Doxorubicin induces apoptosis and necrosis of cardiomyocytes, but the mechanisms underlying these side-effects were far from being completely understood.
The molecular cascade involved in this cardiotoxicity is well described here by Maya Srinivas, using mouse HL-1 cells. HL-1 Cardiac Muscle Cell Line has been extensively characterized and is a valuable model system for addressing questions of cardiac biology at the cellular and molecular levels.
Which receptor is involved? The ErbB2/ErbB4 heterodimer, a member of the neuregulin receptor superfamily.
What triggers the cardioprotective effect? The binding of Glial Growth Factor 2 (GGF2) on this receptor?
Which signaling pathways? Mainly pAKT and pBAD, but also PI3 Kinase.
Now you know now the main players, but you still need more details to understand how this molecular cascade is controlled and can lead to cardioprotection. Let your curiosity guide you!
Neuregulin/erbB signaling is cardioprotective as seen in models of cardiotoxicity associated with the use of chemotherapeutics. Our studies reveal a function of Bcl-2 to protect cardiomyocytes concomitant with GGF2-induced increases in levels of phospho-BAD (pBAD) along with activation of PI3 kinase (PI3K) and MAP kinase (MAPK). We show that phosphorylation of BAD is dependent upon GGF2 mediated activation of PI3K. In addition, examination of mitochondrial gene expression shows several members of the Bcl-2 family are down-regulated by doxorubicin, while GGF2 is able to reverse this effect. While many in vitro model systems of doxorubicin cardiotoxicity have observed PI3K-dependent cytoprotective effects of neuregulin’s, the present results demonstrate that GGF2 mediates cytoprotective actions in HL-1 cardiomyocytes through regulation of mitochondrial mediated apoptosis via the PI3K/Bcl-2 pathway.
Cardiovascular Disorders and Medicine, 2017 Mar; 2(3):1-10.