Alterations of nuclear Ca2+ regulation in ventricular myocytes during development and progression of hypertensive heart disease
Hypertension is the leading risk factor for developing hypertrophy and heart failure. Pathological changes in myocardial structure and function caused by hypertension are termed ’’hypertensive heart disease’’. In response to elevated mechanical stress in hypertension and a special neurohormonal envi...
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|Summary:||Hypertension is the leading risk factor for developing hypertrophy and heart failure. Pathological changes in myocardial structure and function caused by hypertension are termed ’’hypertensive heart disease’’. In response to elevated mechanical stress in hypertension and a special neurohormonal environment (catecholamines, angiotensin II, endothelin-1), the heart grows as a means of increasing pump function and decreasing wall tension thus inducing a state of ’’compensated hypertrophy’’. Initially, hypertrophy is beneficial, but chronic activation of neurohormonal mediators and altered Ca2+ signaling ultimately lead to maladaptive alterations in gene expression and progressive cardiac remodeling, which eventually becomes detrimental and impairs cardiac function. Impairment of Ca2+ handling is critically implicated in the pathophysiology of hypertrophy and heart failure. Two important Ca2+-dependent signaling pathways involved in cardiac remodeling are the Ca2+/calmodulin-dependent protein phosphatase calcineurin (CaN)–NFAT–GATA4/6 and the Ca2+/calmodulin-dependent protein kinase II (CaMKII)–HDAC–MEF2 pathway. The mechanisms by which the cardiomyocytes distinguish between Ca2+ involved in excitation-contraction coupling in the cytoplasm and transcriptional regulation in the nucleus are poorly understood.
While alterations in cytoplasmic Ca2+ regulation have been clearly implicated in the pathophysiology of hypertrophy and heart failure, nucleoplasmic Ca2+ signaling has been studied much less. Increases in nucleoplasmic [Ca2+] may activate Ca2+-dependent enzymes and transcription factors modulating gene expression and may be critical for the pathogenesis of hypertrophy and heart failure. However, there is lack of studies dealing with the regulation and alterations of nucleoplasmic Ca2+ handling under pathophysiological conditions.
We used spontaneously hypertensive rats (SHR) to investigate potential alterations in nuclear Ca2+ handling in response to hypertension. During the course of hypertensive heart disease, very little is known about the onset and progression of hypertrophy and heart failure. We hypothesized that maladaptive remodeling of nuclear structure and nuclear Ca2+ signaling might occur early in hypertension triggering initiation and progression of hypertrophy, and in advanced hypertension contributing to the transition from compensated hypertrophy to heart failure.
Therefore, in the first part of the thesis, we studied early hypertension-induced structural and functional (Ca2+ handling) remodeling of left ventricular (LV) myocytes and nuclei. We found that LV myocytes and nuclei from early hypertensive SHR (≈3 months of age) were already in the stage of compensatory hypertrophy. Cytoplasmic and nucleoplasmic [Ca2+]i transients (CaTs) were enlarged in SHR. The increase in nucleoplasmic Ca2+ exceeded the increase in cytoplasmic Ca2+, suggesting enhanced nuclear Ca2+ signaling in SHR. Ca2+ load of SR and perinuclear Ca2+ stores was also enlarged in SHR, while fractional release from both stores was unaltered. Intranuclear Ca2+ propagation was faster in SHR, associated with preserved density of nuclear envelope invaginations and elevated nuclear expression of nucleoporins and SR-Ca2+-ATPase. Increased nucleoplasmic Ca2+ signaling was associated with activation of the CaMKIIδ–HDAC5 pathway and increased histone acetylation, suggesting increased gene transcription. The observed remodeling of nuclear Ca2+ handling might represent an early event in hypertension that contributes to initiation and progression of pathological hypertrophy in hypertensive heart disease.
In the second part of the thesis, we studied structural and functional nuclear remodeling in advanced hypertension. LV myocytes and nuclei from old SHR (15-25 months of age) were larger compared to young hypertrophic SHR, suggesting further growth of the ventricle with progression of cardiac disease. Cytoplasmic and nucleoplasmic CaTs were augmented (as in young hypertrophic SHR). SR and perinuclear Ca2+ load was increased (as in young hypertrophic SHR). There were profound alterations in the kinetics of both cytoplasmic and nucleoplasmic CaTs. Development of heart failure in old SHR was associated with increased density of nuclear envelope invaginations, faster intranuclear Ca2+ propagation, acceleration of both rise time and tau of decay of nuclear CaTs and alterations in the cytoplasmic protein levels of major Ca2+-regulating proteins. Thus, we identified distinct alterations in nuclear structure and Ca2+ handling during development of heart failure in SHR, providing new insights into mechanisms of nuclear Ca2+ regulation under pathophysiological conditions.
Normalization of nucleoplasmic Ca2+ handling may represent a novel target for the treatment of hypertrophy and heart failure in hypertensive heart disease.|