RESUMEN
Neonatal mouse hearts have transient renewal capacity, which is lost in juvenile and adult stages. In neonatal mouse hearts, myocardial infarction (MI) causes an initial loss of cardiomyocytes. However, it is unclear which type of regulated cell death (RCD) occurs in stressed cardiomyocytes. In the current studies, we induced MI in neonatal and juvenile mouse hearts and showed that ischemic cardiomyocytes primarily undergo ferroptosis, a non-apoptotic and iron-dependent form of RCD. We demonstrated that cardiac fibroblasts (CFs) protect cardiomyocytes from ferroptosis through paracrine effects and direct cell-cell interaction. CFs show strong resistance to ferroptosis due to high ferritin expression. The fibrogenic activity of CFs, typically considered detrimental to heart function, is negatively regulated by paired-like homeodomain 2 (Pitx2) signaling from cardiomyocytes. In addition, Pitx2 prevents ferroptosis in cardiomyocytes by regulating ferroptotic genes. Understanding the regulatory mechanisms of cardiomyocyte survival and death can identify potentially translatable therapeutic strategies for MI.
RESUMEN
Neonatal mouse hearts have transient renewal capacity which is lost in juvenile and adult hearts. After myocardial infarction (MI) in neonatal hearts, an initial loss of cardiomyocytes occurs but it is unclear through which type of regulated cell death (RCD). In the current studies, we induced MI in neonatal and juvenile mouse hearts, and show that ischemic cardiomyocytes primarily undergo ferroptosis, a non-apoptotic and iron-dependent form of RCD. We demonstrate that cardiac fibroblasts (CFs) protect cardiomyocytes from ferroptosis through paracrine factors and direct cell-cell interaction. CFs show strong resistance to ferroptosis due to high ferritin expression. Meanwhile, the fibrogenic role of CFs, typically considered detrimental to heart function, is negatively regulated by paired-like homeodomain 2 (Pitx2) signaling from cardiomyocytes. In addition, Pitx2 prevents ferroptosis in cardiomyocytes by regulating ferroptotic genes. Understanding the regulatory mechanisms of cardiomyocyte survival and death can identify potentially translatable therapeutic strategies for MI.
RESUMEN
Glaucoma is a chronic disease that can be challenging to treat for both patients and physicians. Most patients will require more than 1 medication over time to maintain their intraocular pressure (IOP) at a physiologically benign level. Patients may become refractory to existing compounds and many struggle with adherence to multiple topical drop regimens. The field of glaucoma therapeutics has been advancing rapidly with an emphasis on compounds comprising multiple molecules/mechanisms of action that offer additivity and are complementary to current therapeutics. Several new topical drop compounds directly targeting the trabecular meshwork (TM)/Schlemm canal/conventional outflow pathway to reduce outflow resistance have obtained US Food and Drug Administration approval in the past year. These include rho kinase inhibitors and nitric oxide donating compounds. Alternative therapies that offer long-term IOP lowering while removing the patient from the drug delivery system are moving forward in development. These include gene therapy and stem cell strategies, which could ease or eliminate the burden of topical drop self-administration for several years. Additionally, a variety of novel formulations and devices are in development that aim for controlled, steady state delivery of therapeutics over periods of months. The future of glaucoma therapy is focusing on an increase in specificity for the individual patient: their type of glaucoma; underlying mechanisms; genetic make-up; comorbid conditions; and rate of progression. Maintaining functional vision and improving patient outcomes remains the goal in glaucoma therapeutics. The current collection of novel therapeutics offers an expanded set of tools to achieve that goal.