Failure of Calcineurin Inhibitors to Prevent Pressure-Overload Left Ventricular Hypertrophy in Rats

Abstract

Abstract-A rapidly emerging body of literature implicates a pivotal role for the Ca 2ϩ -calmodulin-dependent phosphatase calcineurin as a cellular target for a variety of Ca 2ϩ -dependent signaling pathways culminating in left ventricular hypertrophy (LVH). Most of the recent experimental support for this hypothesis is derived from in vitro studies or in vivo studies in transgenic mice expressing activated calcineurin or mutant sarcomeric proteins. The aim of the present study was to test whether calcineurin inhibitors, cyclosporin A (CsA) and FK 506, prevent pressure-overload LVH using 2 standard rat models: (1) the spontaneously hypertensive rat (SHR) and (2) aortic banding. The major new findings are 2-fold. First, in SHR, LVH (left ventricular weight to body weight ratio) was unaffected by a dose of CsA (5 mg ⅐ kg Ϫ1 ⅐ d Ϫ1) that was sufficient to raise blood pressure and to inhibit calcineurin-mediated transcriptional activation in skeletal muscle. Second, in rats with aortic banding, LVH was unaffected by FK 506 (0.3 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) or even higher doses of CsA (10 and 20 mg ⅐ kg) that were sufficient to inhibit 90% of total calcineurin phosphatase activity in the hypertrophied myocardium. In the latter experiments, CsA blocked neither the elevated left ventricular end-diastolic pressures, a measure of diastolic function, nor the induction in atrial natriuretic peptide mRNA in the hypertrophic ventricles. Thus, in numerous experiments, systemic administration of potent calcineurin inhibitors did not prevent the development of LVH in 2 classic models of pressure-overload hypertrophy. These results demonstrate that pressureoverload hypertrophy can arise through calcineurin-independent pathways. (Circ Res. 1999;84:722-728.) Key Words: left ventricular hypertrophy Ⅲ calcineurin Ⅲ cyclosporin A Ⅲ spontaneously hypertensive rat Ⅲ aortic banding I n patients with many forms of heart disease, the development of left ventricular hypertrophy (LVH) constitutes one of the most powerful predictors of subsequent cardiovascular morbidity and mortality. 1-3 Increased left ventricular mass strongly predicts an increased incidence of cardiovascular death, myocardial infarction, angina requiring revascularization, stroke, and congestive heart failure. Despite the clinical importance of LVH, the underlying mechanisms mediating the hypertrophic process have been enigmatic.A variety of intrinsic and extrinsic pathological stimuli can initiate a hypertrophic response in the left ventricle. Extrinsic stimuli include pressure overload, volume overload, and neurohumoral factors. Intrinsic stimuli include contractile abnormalities resulting from altered expression or mutations of sarcomeric proteins. Although these diverse stimuli are known to activate diverse intracellular signal transduction pathways, 4 it is unknown whether these various pathways ultimately converge on a final common signaling pathway culminating in cardiomyocyte hypertrophy. 4 -6 In this regard, changes in [Ca 2ϩ ] i have been proposed to play a pivotal rol...

A Protein Encoded within the Down Syndrome Critical Region Is Enriched in Striated Muscles and Inhibits Calcineurin Signaling

“…immunosuppression and hypertension) of existing agents. Calcineurin antagonists also prevent cardiac hypertrophy and heart failure in some, although not all, animal models of acquired forms of cardiomyopathy that are common in human populations (17,50,51), but the same limitations to clinical trials apply. The relative abundance of MCIP1 in cardiac muscle recommends it as a target for drug development to circumvent these limitations of current calcineurin antagonists.…”

Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo

“…However, such reports remain controversial for a number of reasons. First, four studies failed to identify a significant decrease in cardiac hypertrophy in rodent models of pressure overload treated with CsA or FK506 (19)(20)(21)(22). Second, CsA and FK506 are known to have additional biological effects, separate from calcineurin inhibition (23)(24)(25).…”

“…In vivo, three separate mouse models of hypertrophic cardiomyopathy were largely rescued by the administration of CsA or FK506, further implicating this signaling pathway in the heart (9). CsA and FK506 have also been reported to attenuate͞prevent pressure overload-induced cardiac hypertrophy in most (9-18) but not all in vivo studies (19)(20)(21)(22).Although the main biological effects of CsA and FK506 are attributed to calcineurin inhibition, each agent has multiple intracellular targets that are independent of calcineurin (23-25). To block calcineurin activity without using pharmacologic agents, we generated cardiac-restricted Tg mice expressing the calcineurin inhibitory protein domains from Cain͞Cabin-1 and A-kinase-anchoring protein 79 (AKAP79) (26-28).…”

“…In vivo, three separate mouse models of hypertrophic cardiomyopathy were largely rescued by the administration of CsA or FK506, further implicating this signaling pathway in the heart (9). CsA and FK506 have also been reported to attenuate͞prevent pressure overload-induced cardiac hypertrophy in most (9-18) but not all in vivo studies (19)(20)(21)(22).…”

Calcineurin Blockade Prevents Cardiac Mitogen-activated Protein Kinase Activation and Hypertrophy in Renovascular Hypertension

“…Similarly, CaN is suggested to be involved in the cardiac expression of the immediate response genes in the hypertrophied heart (16). However, the exact role of CaN in mediating Ang II-dependent cardiac growth in vivo remains to be established (17)(18)(19)(20)(21).…”