Novel Approaches to Protect the Heart Following Injury
Researchers here discuss potential approaches to protect the heart from scarring and loss of function following a heart attack: senolytics to clear senescent cells; restoration of mitochondrial function; induction of telomerase activity; and inhibition of inflammatory signaling. Removing the cause of heart attacks by finding a cure for atherosclerosis, a way to reverse the fatty lesions that narrow blood vessels and weaken blood vessel walls, would be preferable to finding better ways to fixing the damage after the fact. But there will always be some call for ways to improve the regenerative capacity of an injured heart.
The hallmarks of myocardial aging may account for the reduced tolerance against myocardial ischemia/reperfusion injury in preclinical studies and thus, understanding mechanisms of myocardial aging may enable the development of new and effective therapies to reduce cardiac damage after myocardial infarction (MI) in the context of aging.
Senescent cells increase in aged tissues, which has been associated with the progression of age-related diseases. In this context, senescence markers are augmented in aged cardiomyocytes, which has been linked to higher risk of cardiovascular diseases. Senolytics are agents that can selectively target pro-survival proteins of senescent cells, inducing cell death. Regarding the heart, there are three major senolytics that have been widely studied in vivo and in vitro; Dasatinib, Quercetin, and Navitoclax. These senolytics have been shown to improve vascular function. Importantly, a study showed that oral administration of navitoclax to aged mice before in vivo myocardial infarction reduced mortality, as well as age-related myocardial remodeling and improved left ventricular function.
The mitochondria have been identified as an important target to reduce myocardial ischemia/reperfusion injury in the aged heart. The mitochondria in aging cardiomyocytes shows elevated ROS production, higher fragmentation and reduced biogenesis, thus producing mitochondrial dysfunction, which can contribute to the increased susceptibility of the aged heart to ischemic injury. Therefore, therapies targeting the mitochondria are an attractive area of research in cardioprotection.
During MI, a pathogen/antigen-independent inflammatory response, known as sterile inflammation, takes place. Due to the rupture in the cellular structure that occurs during MI, damage-associated molecular patterns (DAMPS) mediators are released and are recognized by pattern recognition receptors (PRRs), which in turn mediate the initiation of the inflammatory response. NLPR3 inflammasome is a multiprotein complex formed by the activation of PRRs, thereby increasing the production and release of proinflammatory cytokines via activation of caspase-1. Interestingly, pharmacological inhibition of caspase-1 reduced the infarct size in isolated rat hearts. Also, caspase-1 inhibition was also shown to provide additional protection when combined with remote ischemic preconditioning in rats subjected to in vivo myocardial infarction.
Telomeres are repeated hexanucleotide sequences at the end of eukaryotic chromosomes. Their presence is associated with DNA protection during cell division. Division of the cell as well as oxidative stress shortens these structures, leading the cell to a senescent state or apoptosis. Telomere length has been associated with coronary artery disease and therefore, it has been proposed as a biomarker for cardiovascular diseases. Telomerase is a key regulator of telomere length and integrity and as such, has gained attention for its potential benefits in age-related cardiovascular diseases. For instance, absence of telomerase has been associated with increased susceptibility to ischemic injury. By the same token, overexpression of telomerase can confer cardioprotection in mice hearts.