Making a case for metallothioneins conferring cardioprotection in pulmonary hypertension.

Pulmonary hypertension (PH) is defined as elevated mean pulmonary artery pressure secondary to e.g. congenital heart disease and chronic obstructive pulmonary disease. It elevates right ventricular afterload that eventually leads to cor pulmonale and right heart failure. Experimental research has shown that cardioprotective strategies may improve morbidity and reduce mortality in PH patients. PH and consequent right heart failure are underpinned by dysregulated mitochondrial dynamics, and therefore mitochondrial regulators may be targeted as cardioprotective agents in PH. Mitochondrial regulators such as the metallothioneins (MTs) confer cardioprotection against several forms of heart/lung disease. Furthermore, MT expression is up or downregulated in biopsies or blood from patients with PH. However, despite the overwhelming evidence that MT has potential as cardioprotective agents in PH, MT-induced cardioprotection has not been tested in experimental models of PH. Therefore, it is necessary to evaluate the attributes of MTs that make them candidates for cardioprotection in PH. The hypothesis presented in this paper is that upregulation of cardiac MTs can confer cardioprotection in PH and associated right ventricular remodelling. Mainly due to their ability to detoxify the myocardium of excess heavy metals, scavenging of free radicals and modulation of mitochondrial dynamics. These processes are instrumental in the development of PH and right ventricular remodelling. With this hypothesis we propose that the upregulation of cardiac MTs can confer cardioprotection in PH by detoxifying the myocardium of heavy metals and improving cardiac mitochondrial efficiency (i.e. reducing ROS, reducing oxidative stress, and improving antioxidant capacity and improving mitochondrial respiration).