Pretreatment with ambrisentan, a selective endothelin A receptor antagonist approved for pulmonary arterial hypertension, significantly protected H9c2 cardiomyoblasts from doxorubicin-induced damage by suppressing pro-apoptotic markers (p-p53/p53, BAX), reducing cytosolic and mitochondrial reactive oxygen species, restoring mitochondrial membrane potential, and upregulating pro-survival regulators including Bcl-2, PGC1α, NRF1, OPA1, and mTOR-associated proteins Rictor and Raptor. Pharmacological confirmation using the p53 inhibitor pifithrin-α and mTOR inhibitor rapamycin validated p53 and mTOR as mechanistic mediators of ambrisentan's cardioprotective effects.
Doxorubicin remains among oncology's most effective yet cardiotoxic agents, with cumulative cardiomyopathy affecting a meaningful fraction of long-term cancer survivors — a growing population urgently needing cardio-oncology solutions. This study's mechanistic granularity is notable: it connects endothelin receptor blockade to mitochondrial biogenesis machinery (PGC1α, NRF1), fusion dynamics (OPA1), and bioenergetic output (ATP5A), suggesting a broader mitochondrial remodeling effect rather than simple anti-apoptotic signaling. The simultaneous suppression of Beclin-1 implies modulation of autophagy flux as well.
However, critical limitations temper enthusiasm. H9c2 cells are rat embryonic cardiac myoblasts — not fully differentiated adult cardiomyocytes — making extrapolation to human cardiac physiology speculative. No in vivo validation is presented, and causality through the p53/mTOR axes remains correlative. Still, repurposing an already-approved, orally bioavailable drug for chemotherapy-related cardiac protection is a strategically compelling direction warranting rigorous animal and clinical investigation.