Right ventricular (RV) failure is a serious common clinical problem that is poorly understood. Therefore, for failing and nonfailing hearts, we examined the distinctive inotropic responses induced in the RV myocardium after the stimulation of ␣ 1-adrenergic receptors (ARs). In RV trabeculae from nonfailing mouse hearts, ␣ 1-ARs induced a negative inotropic response, consistent with our previous study. In marked contrast, in RV trabeculae from failing hearts, 12 wk after coronary artery ligation, ␣1-ARs induced a positive inotropic response. Mechanistically, experiments with skinned trabeculae showed that ␣1-ARs decreased myofilament Ca 2ϩ sensitivity in the nonfailing RV myocardium, whereas ␣1-ARs increased Ca 2ϩ sensitivity in heart failure. This suggests that a switch in the Ca 2ϩ sensitivity response to ␣1-AR stimulation explained the switch in the RV ␣1-AR inotropic response in heart failure. Myosin light chain kinase (MLCK) can increase myofilament Ca 2ϩ sensitivity, and the smooth muscle isoform (smMLCK), which is also present in cardiomyocytes, was more abundant in the RV myocardium from failing versus nonfailing hearts. Moreover, the MLCK inhibitor ML-9 prevented the switch of the RV myocardium to a positive ␣1-AR inotropic response in heart failure. In the left ventricular myocardium, in contrast, ␣1-AR inotropic responses were not different in failing versus nonfailing hearts, and smMLCK abundance was not increased in heart failure. In relation to human disease, we found that smMLCK mRNA and protein levels were increased in RVs from failing human hearts. We conclude that the RV inotropic response to ␣1-ARs is switched from negative to positive in heart failure, through a pathway involving increased myofilament Ca 2ϩ sensitivity. Since ␣1-AR agonist catecholamines are elevated in heart failure, increased ␣1-AR inotropic responses in the RV myocardium may be adaptive in heart failure by helping the failing RV respond to increased pulmonary pressures. right ventricle; myosin light chain kinase; myofilament calcium sensitivy RIGHT VENTRICULAR (RV) failure is a prevalent cause of cardiovascular collapse and a major public health problem (14,20). RV failure frequently arises in patients with left ventricular (LV) failure and causes markedly worse symptoms and prognosis compared with patients with LV failure without RV dysfunction (9,11,13). Moreover, the prognosis of heart failure patients with pulmonary hypertension is strongly related to RV dysfunction (13).Despite its clinical significance, RV failure is relatively understudied and poorly understood (31). The RV has been viewed merely as a weak LV (14). Conversely, we (33) reported that the RV and LV have fundamentally different inotropic responses to stimulation of ␣ 1 -adrenergic receptors (ARs), which caused negative inotropic responses in the RV myocardium but positive inotropic responses in the LV myocardium. This and another study (31) have indicated that the RV and LV are categorically different and that RV failure cannot be understood by extrapola...

L-Plastin is normally a leukocyte-specific actin-binding protein; it is also expressed in the majority of human cancer cell lines that are derived from many types of solid tumors. We have previously reported the isolation of the L-plastin gene promoter, in which we identified several potential steroid receptor-binding sequences. We now obtained evidence that L-plastin gene expression was positively regulated by testosterone in androgen receptor (AR)-positive prostate and breast cancer cells. DNase I footprint analysis identified three AR-binding elements (ARE) located in a 545-bp region approximately 1.1 kb upstream from the transcription initiation site. However, each of these three AREs exhibited very little testosterone/AR-responsive enhancer activities toward a test promoter (of the thymidine kinase gene) when tested in MCF-7 breast cancer cells. Their testosterone/AR responsiveness became evident only when two or three of them were combined. In PC-3 prostate cancer cells, cooperation among L-plastin AREs was still evident although individually they had moderate levels of testosterone/AR responsiveness. Thus, the three L-plastin AREs, despite their imperfect sequences compared with the consensus ARE, could cooperate with each other to become a potent testosterone/AR-responsive unit, which was likely responsible for the inducibility of the L-plastin gene by testosterone.