An emerging role for the Cdk-inhibitors p21Cip1/Waf1 and p27Kip1 as potential therapies for the treatment of cardiac hypertrophy

Abstract

Heart failure is the leading cause of morbidity and mortality worldwide. Adult cardiomyocytes are post-mitotic cells that are substantially refractory to re-enter the cell cycle. This is exemplified by the absence of significant proliferative potential in differentiated cardiomyocytes. When exposed to aberrant growth stimuli, cardiomyocytes undergo maladaptive changes characterized by hypertrophic growth. The existing armamentarium of conventional pharmacological therapy can only slow the progression of the disease by alleviating the workload of the heart. Various agonist- and stress-induced extracellular signal transduction pathways could be target by novel agents for the treatment of pathological cardiac growth. Among these, the cyclin-dependent kinase inhibitors p21 and p27 have been recognized as potent inhibitors of apoptosis, growth and proliferation in cardiovascular disease. The role of the cell cycle factors p21 and p27 in the regulation of growth-associated processes in the heart, and their potential therapeutic implications are not immediately obvious, as it is the case in cardiovascular biology. In this review, we focus on the multiple functions of p21 and p27 in the regulation of hypertrophy, and briefly discuss pathways that play critical play therein. All these selected studies attest an important role of p21 and p27 in the regulation of hypertrophy in isolated rat cardiomyocytes, and in various genetic murine models of heart failure. The available evidence suggests that therapeutic clinical approaches involving p21 and p27 have the potential to to treat heart failure in patients.