Alicia Mattiazzi - Academia.edu (original) (raw)

Papers by Alicia Mattiazzi

Research paper thumbnail of Ca2+ mishandling and mitochondrial dysfunction: a converging road to prediabetic and diabetic cardiomyopathy

Pflügers Archiv - European Journal of Physiology, 2022

Research paper thumbnail of Determinants of Ca2+ release restitution: Insights from genetically altered animals and mathematical modeling

Journal of General Physiology, 2020

Each heartbeat is followed by a refractory period. Recovery from refractoriness is known as Ca2+ ... more Each heartbeat is followed by a refractory period. Recovery from refractoriness is known as Ca2+ release restitution (CRR), and its alterations are potential triggers of Ca2+ arrhythmias. Although the control of CRR has been associated with SR Ca2+ load and RYR2 Ca2+ sensitivity, the relative role of some of the determinants of CRR remains largely undefined. An intriguing point, difficult to dissect and previously neglected, is the possible independent effect of SR Ca2+ content versus the velocity of SR Ca2+ refilling on CRR. To assess these interrogations, we used isolated myocytes with phospholamban (PLN) ablation (PLNKO), knock-in mice with pseudoconstitutive CaMKII phosphorylation of RYR2 S2814 (S2814D), S2814D crossed with PLNKO mice (SDKO), and a previously validated human cardiac myocyte model. Restitution of cytosolic Ca2+ (Fura-2 AM) and L-type calcium current (ICaL; patch-clamp) was evaluated with a two-pulse (S1/S2) protocol. CRR and ICaL restitution increased as a functi...

Research paper thumbnail of Tracking nitroxyl-derived posttranslational modifications of phospholamban in cardiac myocytes

Journal of General Physiology, 2019

Mundiña-Weilenmann and Mattiazzi examine new work revealing the mechanism by which nitroxide modi... more Mundiña-Weilenmann and Mattiazzi examine new work revealing the mechanism by which nitroxide modifies uptake of Ca2+ into the SR.

Research paper thumbnail of Endoplasmic reticulum contribution to the relaxant effect of cGMP- and cAMP-elevating agents in feline aorta

American Journal of Physiology-Heart and Circulatory Physiology, 2000

The contribution of endoplasmic reticulum (ER) and phosphorylation of phospholamban (PLB) to the ... more The contribution of endoplasmic reticulum (ER) and phosphorylation of phospholamban (PLB) to the relaxant effect of cGMP- and cAMP-elevating agents was studied in feline aorta. Sodium nitroprusside (NP, 100 μM) completely relaxed contracture induced by 10 μM norepinephrine. This NP-induced relaxation was partially prevented by tetraethylammonium, suggesting that a fraction of NP-induced relaxation was mediated by activation of K+channels. In the absence and presence of tetraethylammonium, the relaxant effect of NP was associated with a significant increase in Ser16phosphorylation of PLB immunodetected by phosphorylation site-specific antibodies. The relaxant effect of NP on aortic strips precontracted with 80 mM KCl was significantly reduced by 1 μM thapsigargin. This decrease, which represents the ER contribution to the relaxant effect of NP, reached 23 ± 9% at 100 μM NP and was closely associated with a dose-dependent increase in Ser16phosphorylation (128 ± 49% over control at 100...

Research paper thumbnail of Ablation of PLN rescues reperfusion arrhythmias but exacerbates myocardium infarction in hearts with Ca2+/calmodulin kinase II constitutive phosphorylation of ryanodine receptors

Cardiovascular research, Jan 29, 2018

Abnormal Ca2+ release from the sarcoplasmic reticulum (SR), associated with CaMKII-dependent phos... more Abnormal Ca2+ release from the sarcoplasmic reticulum (SR), associated with CaMKII-dependent phosphorylation of RyR2 at Ser2814, has consistently been linked to arrhythmogenesis and ischemia/reperfusion-induced cell death. In contrast, the role played by SR Ca2+ uptake under these stress conditions remains controversial. We tested the hypothesis that an increase in SR Ca2+ uptake is able to attenuate reperfusion arrhythmias and cardiac injury elicited by increased RyR2-Ser2814 phosphorylation. We used WT mice, which have been previously shown to exhibit a transient increase in RyR2-Ser2814 phosphorylation at the onset of reperfusion; mice with constitutive pseudo-phosphorylation of RyR2 at Ser2814 (S2814D) to exacerbate CaMKII-dependent reperfusion arrhythmias and cardiac damage, and PLN-deficient-S2814D knock-in mice (SDKO) resulting from crossbreeding S2814D with PLN deficient mice (PLNKO). At baseline, S2814D and SDKO mice had structurally normal hearts. Moreover none of the stra...

Research paper thumbnail of Non-β-Blocking Carvedilol Analog, VK-II-86, Prevents Ouabain-Induced Cardiotoxicity

Circulation journal : official journal of the Japanese Circulation Society, Jan 23, 2018

It has been shown that carvedilol and its non β-blocking analog, VK-II-86, inhibit spontaneous Ca... more It has been shown that carvedilol and its non β-blocking analog, VK-II-86, inhibit spontaneous Ca release from the sarcoplasmic reticulum (SR). The aim of this study is to determine whether carvedilol and VK-II-86 suppress ouabain-induced arrhythmogenic Ca waves and apoptosis in cardiac myocytes. Methods and Results: Rat cardiac myocytes were exposed to toxic doses of ouabain (50 µmol/L). Cell length (contraction) was monitored in electrically stimulated and non-stimulated conditions. Ouabain treatment increased contractility, frequency of spontaneous contractions and apoptosis compared to control cells. Carvedilol (1 µmol/L) or VK-II-86 (1 µmol/L) did not affect ouabain-induced inotropy, but significantly reduced the frequency of Ca waves, spontaneous contractions and cell death evoked by ouabain treatment. This antiarrhythmic effect was not associated with a reduction in Ca calmodulin-dependent protein kinase II (CaMKII) activity, phospholamban and ryanodine receptor phosphorylati...

Research paper thumbnail of Impact of RyR2 potentiation on myocardial function

American Journal of Physiology-Heart and Circulatory Physiology, 2017

This perspective attempts to shed light on an old and not yet solved controversy in cardiac physi... more This perspective attempts to shed light on an old and not yet solved controversy in cardiac physiology, i.e., the impact of increasing ryanodine receptor (RyR)2 open probability on myocardial function. Based on an already proven myocyte model, it was shown that increasing RyR2 open probability results in a purely short-lived increase in Ca2+transient amplitude, and, therefore, it does not increase cardiac contractility. However, potentiation of RyR2 activity permanently enhances fractional Ca2+release, shifting the intracellular Ca2+transient versus sarcoplasmic reticulum (SR) Ca2+content curve to a new state of higher efficiency. This would allow the heart to maintain a given contractility despite a decrease in SR Ca2+content, to enhance contractility if SR Ca2+content is simultaneously preserved or to successfully counteract the effects of a negative inotropic intervention.NEW & NOTEWORTHY Increasing ryanodine receptor (RyR)2 open probability does not increase cardiac contractilit...

Research paper thumbnail of Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII‐constitutive phosphorylation of RyR2 at site S2814

The Journal of Physiology, 2016

Key points Mice with Ca2+–calmodulin‐dependent protein kinase (CaMKII) constitutive pseudo‐phosph... more Key points Mice with Ca2+–calmodulin‐dependent protein kinase (CaMKII) constitutive pseudo‐phosphorylation of the ryanodine receptor RyR2 at Ser2814 (S2814D+/+ mice) exhibit a higher open probability of RyR2, higher sarcoplasmic reticulum (SR) Ca2+ leak in diastole and increased propensity to arrhythmias under stress conditions. We generated phospholamban (PLN)‐deficient S2814D+/+ knock‐in mice by crossing two colonies, S2814D+/+ and PLNKO mice, to test the hypothesis that PLN ablation can prevent the propensity to arrhythmias of S2814D+/+ mice. PLN ablation partially rescues the altered intracellular Ca2+ dynamics of S2814D+/+ hearts and myocytes, but enhances SR Ca2+ sparks and leak on confocal microscopy. PLN ablation diminishes ventricular arrhythmias promoted by CaMKII phosphorylation of S2814 on RyR2. PLN ablation aborts the arrhythmogenic SR Ca2+ waves of S2814D+/+ and transforms them into non‐propagating events. A mathematical human myocyte model replicates these results and...

Research paper thumbnail of Ryanodine receptor phosphorylation by CaMKII promotes spontaneous Ca2+ release events in a rodent model of early stage diabetes: The arrhythmogenic substrate

International Journal of Cardiology, 2016

Research paper thumbnail of Calcium-Calmodulin Kinase II Mediates Digitalis-Induced Arrhythmias

Circulation: Arrhythmia and Electrophysiology, 2011

Background— Digitalis-induced Na + accumulation results in an increase in Ca 2+ i via the Na + /C... more Background— Digitalis-induced Na + accumulation results in an increase in Ca 2+ i via the Na + /Ca 2+ exchanger, leading to enhanced sarcoplasmic reticulum (SR) Ca 2+ load, responsible for the positive inotropic and toxic arrhythmogenic effects of glycosides. A digitalis-induced increase in Ca 2+ i could also activate calcium-calmodulin kinase II (CaMKII), which has been shown to have proarrhythmic effects. Here, we investigate whether CaMKII underlies digitalis-induced arrhythmias and the subcellular mechanisms involved. Methods and Results— In paced rat ventricular myocytes (0.5 Hz), 50 μmol/L ouabain increased contraction amplitude by 160±5%. In the absence of electric stimulation, ouabain promoted spontaneous contractile activity and Ca 2+ waves. Ouabain activated CaMKII (p-CaMKII), which phosphorylated its downstream targets, phospholamban (PLN) (Thr17) and ryanodine receptor (RyR) (Ser2814). Ouabain-induced spontaneous activity was prevented by inhibiting CaMKII with 2.5 μmol/...

Research paper thumbnail of CaMKII-dependent phosphorylation of cardiac ryanodine receptors regulates cell death in cardiac ischemia/reperfusion injury

Journal of Molecular and Cellular Cardiology, 2014

Research paper thumbnail of Ca2+ Sparks and Ca2+ waves are the subcellular events underlying Ca2+ overload during ischemia and reperfusion in perfused intact hearts

Journal of Molecular and Cellular Cardiology, 2015

Research paper thumbnail of Aging and CaMKII Alter Intracellular Ca2+ Transients and Heart Rhythm in Drosophila melanogaster

Research paper thumbnail of Increased Na+/Ca2+ Exchanger Expression/Activity Constitutes a Point of Inflection in the Progression to Heart Failure of Hypertensive Rats

Research paper thumbnail of β2-Adrenergic stimulation is involved in the contractile dysfunction of the stunned heart

Naunyn-Schmiedeberg's Archives of Pharmacology, 2006

Research paper thumbnail of Lusitropic effects of α- and β-adrenergic stimulation in amphibian heart

Molecular and Cellular Biochemistry, 1994

Research paper thumbnail of The signalling pathway of CaMKII-mediated apoptosis and necrosis in the ischemia/reperfusion injury

Journal of Molecular and Cellular Cardiology, 2010

Research paper thumbnail of Mechanisms Involved in the Acidosis Enhancement of the Isoproterenol-induced Phosphorylation of Phospholamban in the Intact Heart

Journal of Biological Chemistry, 1998

Research paper thumbnail of Immunodetection of Phosphorylation Sites Gives New Insights into the Mechanisms Underlying Phospholamban Phosphorylation in the Intact Heart

Journal of Biological Chemistry, 1996

Research paper thumbnail of Early apoptosis in different models of cardiac hypertrophy induced by high renin-angiotensin system activity involves CaMKII

Journal of Applied Physiology, 2012

The objective of this study was to establish whether 1) hyperactivity of renin-angiotensin-aldost... more The objective of this study was to establish whether 1) hyperactivity of renin-angiotensin-aldosterone system (RAAS) produces apoptosis in early stages of cardiac disease; and 2) Ca2+-calmodulin-dependent protein kinase II (CaMKII) is involved in these apoptotic events. Two models of hypertrophy were used at an early stage of cardiac disease: spontaneously hypertensive rats (SHR) and isoproterenol-treated rats (Iso-rats). At 4 mo, SHR showed blood pressure, aldosterone serum levels, used as RAAS activity index, and left ventricular mass index, used as hypertrophy index, above control values by 84.2 ± 2.6 mmHg, 211.2 ± 25.8%, and 8.6 ± 1.1 mg/mm, respectively. There was also an increase in apoptotis (Bax-to-Bcl-2 ratio and terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling positive cells) associated with an enhancement of CaMKII activity with respect to age-matched controls (phosphorylated-CaMKII, 98.7 ± 14.1 above control). Similar results were observed in 4-mo-ol...

Research paper thumbnail of Ca2+ mishandling and mitochondrial dysfunction: a converging road to prediabetic and diabetic cardiomyopathy

Pflügers Archiv - European Journal of Physiology, 2022

Research paper thumbnail of Determinants of Ca2+ release restitution: Insights from genetically altered animals and mathematical modeling

Journal of General Physiology, 2020

Each heartbeat is followed by a refractory period. Recovery from refractoriness is known as Ca2+ ... more Each heartbeat is followed by a refractory period. Recovery from refractoriness is known as Ca2+ release restitution (CRR), and its alterations are potential triggers of Ca2+ arrhythmias. Although the control of CRR has been associated with SR Ca2+ load and RYR2 Ca2+ sensitivity, the relative role of some of the determinants of CRR remains largely undefined. An intriguing point, difficult to dissect and previously neglected, is the possible independent effect of SR Ca2+ content versus the velocity of SR Ca2+ refilling on CRR. To assess these interrogations, we used isolated myocytes with phospholamban (PLN) ablation (PLNKO), knock-in mice with pseudoconstitutive CaMKII phosphorylation of RYR2 S2814 (S2814D), S2814D crossed with PLNKO mice (SDKO), and a previously validated human cardiac myocyte model. Restitution of cytosolic Ca2+ (Fura-2 AM) and L-type calcium current (ICaL; patch-clamp) was evaluated with a two-pulse (S1/S2) protocol. CRR and ICaL restitution increased as a functi...

Research paper thumbnail of Tracking nitroxyl-derived posttranslational modifications of phospholamban in cardiac myocytes

Journal of General Physiology, 2019

Mundiña-Weilenmann and Mattiazzi examine new work revealing the mechanism by which nitroxide modi... more Mundiña-Weilenmann and Mattiazzi examine new work revealing the mechanism by which nitroxide modifies uptake of Ca2+ into the SR.

Research paper thumbnail of Endoplasmic reticulum contribution to the relaxant effect of cGMP- and cAMP-elevating agents in feline aorta

American Journal of Physiology-Heart and Circulatory Physiology, 2000

The contribution of endoplasmic reticulum (ER) and phosphorylation of phospholamban (PLB) to the ... more The contribution of endoplasmic reticulum (ER) and phosphorylation of phospholamban (PLB) to the relaxant effect of cGMP- and cAMP-elevating agents was studied in feline aorta. Sodium nitroprusside (NP, 100 μM) completely relaxed contracture induced by 10 μM norepinephrine. This NP-induced relaxation was partially prevented by tetraethylammonium, suggesting that a fraction of NP-induced relaxation was mediated by activation of K+channels. In the absence and presence of tetraethylammonium, the relaxant effect of NP was associated with a significant increase in Ser16phosphorylation of PLB immunodetected by phosphorylation site-specific antibodies. The relaxant effect of NP on aortic strips precontracted with 80 mM KCl was significantly reduced by 1 μM thapsigargin. This decrease, which represents the ER contribution to the relaxant effect of NP, reached 23 ± 9% at 100 μM NP and was closely associated with a dose-dependent increase in Ser16phosphorylation (128 ± 49% over control at 100...

Research paper thumbnail of Ablation of PLN rescues reperfusion arrhythmias but exacerbates myocardium infarction in hearts with Ca2+/calmodulin kinase II constitutive phosphorylation of ryanodine receptors

Cardiovascular research, Jan 29, 2018

Abnormal Ca2+ release from the sarcoplasmic reticulum (SR), associated with CaMKII-dependent phos... more Abnormal Ca2+ release from the sarcoplasmic reticulum (SR), associated with CaMKII-dependent phosphorylation of RyR2 at Ser2814, has consistently been linked to arrhythmogenesis and ischemia/reperfusion-induced cell death. In contrast, the role played by SR Ca2+ uptake under these stress conditions remains controversial. We tested the hypothesis that an increase in SR Ca2+ uptake is able to attenuate reperfusion arrhythmias and cardiac injury elicited by increased RyR2-Ser2814 phosphorylation. We used WT mice, which have been previously shown to exhibit a transient increase in RyR2-Ser2814 phosphorylation at the onset of reperfusion; mice with constitutive pseudo-phosphorylation of RyR2 at Ser2814 (S2814D) to exacerbate CaMKII-dependent reperfusion arrhythmias and cardiac damage, and PLN-deficient-S2814D knock-in mice (SDKO) resulting from crossbreeding S2814D with PLN deficient mice (PLNKO). At baseline, S2814D and SDKO mice had structurally normal hearts. Moreover none of the stra...

Research paper thumbnail of Non-β-Blocking Carvedilol Analog, VK-II-86, Prevents Ouabain-Induced Cardiotoxicity

Circulation journal : official journal of the Japanese Circulation Society, Jan 23, 2018

It has been shown that carvedilol and its non β-blocking analog, VK-II-86, inhibit spontaneous Ca... more It has been shown that carvedilol and its non β-blocking analog, VK-II-86, inhibit spontaneous Ca release from the sarcoplasmic reticulum (SR). The aim of this study is to determine whether carvedilol and VK-II-86 suppress ouabain-induced arrhythmogenic Ca waves and apoptosis in cardiac myocytes. Methods and Results: Rat cardiac myocytes were exposed to toxic doses of ouabain (50 µmol/L). Cell length (contraction) was monitored in electrically stimulated and non-stimulated conditions. Ouabain treatment increased contractility, frequency of spontaneous contractions and apoptosis compared to control cells. Carvedilol (1 µmol/L) or VK-II-86 (1 µmol/L) did not affect ouabain-induced inotropy, but significantly reduced the frequency of Ca waves, spontaneous contractions and cell death evoked by ouabain treatment. This antiarrhythmic effect was not associated with a reduction in Ca calmodulin-dependent protein kinase II (CaMKII) activity, phospholamban and ryanodine receptor phosphorylati...

Research paper thumbnail of Impact of RyR2 potentiation on myocardial function

American Journal of Physiology-Heart and Circulatory Physiology, 2017

This perspective attempts to shed light on an old and not yet solved controversy in cardiac physi... more This perspective attempts to shed light on an old and not yet solved controversy in cardiac physiology, i.e., the impact of increasing ryanodine receptor (RyR)2 open probability on myocardial function. Based on an already proven myocyte model, it was shown that increasing RyR2 open probability results in a purely short-lived increase in Ca2+transient amplitude, and, therefore, it does not increase cardiac contractility. However, potentiation of RyR2 activity permanently enhances fractional Ca2+release, shifting the intracellular Ca2+transient versus sarcoplasmic reticulum (SR) Ca2+content curve to a new state of higher efficiency. This would allow the heart to maintain a given contractility despite a decrease in SR Ca2+content, to enhance contractility if SR Ca2+content is simultaneously preserved or to successfully counteract the effects of a negative inotropic intervention.NEW & NOTEWORTHY Increasing ryanodine receptor (RyR)2 open probability does not increase cardiac contractilit...

Research paper thumbnail of Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII‐constitutive phosphorylation of RyR2 at site S2814

The Journal of Physiology, 2016

Key points Mice with Ca2+–calmodulin‐dependent protein kinase (CaMKII) constitutive pseudo‐phosph... more Key points Mice with Ca2+–calmodulin‐dependent protein kinase (CaMKII) constitutive pseudo‐phosphorylation of the ryanodine receptor RyR2 at Ser2814 (S2814D+/+ mice) exhibit a higher open probability of RyR2, higher sarcoplasmic reticulum (SR) Ca2+ leak in diastole and increased propensity to arrhythmias under stress conditions. We generated phospholamban (PLN)‐deficient S2814D+/+ knock‐in mice by crossing two colonies, S2814D+/+ and PLNKO mice, to test the hypothesis that PLN ablation can prevent the propensity to arrhythmias of S2814D+/+ mice. PLN ablation partially rescues the altered intracellular Ca2+ dynamics of S2814D+/+ hearts and myocytes, but enhances SR Ca2+ sparks and leak on confocal microscopy. PLN ablation diminishes ventricular arrhythmias promoted by CaMKII phosphorylation of S2814 on RyR2. PLN ablation aborts the arrhythmogenic SR Ca2+ waves of S2814D+/+ and transforms them into non‐propagating events. A mathematical human myocyte model replicates these results and...

Research paper thumbnail of Ryanodine receptor phosphorylation by CaMKII promotes spontaneous Ca2+ release events in a rodent model of early stage diabetes: The arrhythmogenic substrate

International Journal of Cardiology, 2016

Research paper thumbnail of Calcium-Calmodulin Kinase II Mediates Digitalis-Induced Arrhythmias

Circulation: Arrhythmia and Electrophysiology, 2011

Background— Digitalis-induced Na + accumulation results in an increase in Ca 2+ i via the Na + /C... more Background— Digitalis-induced Na + accumulation results in an increase in Ca 2+ i via the Na + /Ca 2+ exchanger, leading to enhanced sarcoplasmic reticulum (SR) Ca 2+ load, responsible for the positive inotropic and toxic arrhythmogenic effects of glycosides. A digitalis-induced increase in Ca 2+ i could also activate calcium-calmodulin kinase II (CaMKII), which has been shown to have proarrhythmic effects. Here, we investigate whether CaMKII underlies digitalis-induced arrhythmias and the subcellular mechanisms involved. Methods and Results— In paced rat ventricular myocytes (0.5 Hz), 50 μmol/L ouabain increased contraction amplitude by 160±5%. In the absence of electric stimulation, ouabain promoted spontaneous contractile activity and Ca 2+ waves. Ouabain activated CaMKII (p-CaMKII), which phosphorylated its downstream targets, phospholamban (PLN) (Thr17) and ryanodine receptor (RyR) (Ser2814). Ouabain-induced spontaneous activity was prevented by inhibiting CaMKII with 2.5 μmol/...

Research paper thumbnail of CaMKII-dependent phosphorylation of cardiac ryanodine receptors regulates cell death in cardiac ischemia/reperfusion injury

Journal of Molecular and Cellular Cardiology, 2014

Research paper thumbnail of Ca2+ Sparks and Ca2+ waves are the subcellular events underlying Ca2+ overload during ischemia and reperfusion in perfused intact hearts

Journal of Molecular and Cellular Cardiology, 2015

Research paper thumbnail of Aging and CaMKII Alter Intracellular Ca2+ Transients and Heart Rhythm in Drosophila melanogaster

Research paper thumbnail of Increased Na+/Ca2+ Exchanger Expression/Activity Constitutes a Point of Inflection in the Progression to Heart Failure of Hypertensive Rats

Research paper thumbnail of β2-Adrenergic stimulation is involved in the contractile dysfunction of the stunned heart

Naunyn-Schmiedeberg's Archives of Pharmacology, 2006

Research paper thumbnail of Lusitropic effects of α- and β-adrenergic stimulation in amphibian heart

Molecular and Cellular Biochemistry, 1994

Research paper thumbnail of The signalling pathway of CaMKII-mediated apoptosis and necrosis in the ischemia/reperfusion injury

Journal of Molecular and Cellular Cardiology, 2010

Research paper thumbnail of Mechanisms Involved in the Acidosis Enhancement of the Isoproterenol-induced Phosphorylation of Phospholamban in the Intact Heart

Journal of Biological Chemistry, 1998

Research paper thumbnail of Immunodetection of Phosphorylation Sites Gives New Insights into the Mechanisms Underlying Phospholamban Phosphorylation in the Intact Heart

Journal of Biological Chemistry, 1996

Research paper thumbnail of Early apoptosis in different models of cardiac hypertrophy induced by high renin-angiotensin system activity involves CaMKII

Journal of Applied Physiology, 2012

The objective of this study was to establish whether 1) hyperactivity of renin-angiotensin-aldost... more The objective of this study was to establish whether 1) hyperactivity of renin-angiotensin-aldosterone system (RAAS) produces apoptosis in early stages of cardiac disease; and 2) Ca2+-calmodulin-dependent protein kinase II (CaMKII) is involved in these apoptotic events. Two models of hypertrophy were used at an early stage of cardiac disease: spontaneously hypertensive rats (SHR) and isoproterenol-treated rats (Iso-rats). At 4 mo, SHR showed blood pressure, aldosterone serum levels, used as RAAS activity index, and left ventricular mass index, used as hypertrophy index, above control values by 84.2 ± 2.6 mmHg, 211.2 ± 25.8%, and 8.6 ± 1.1 mg/mm, respectively. There was also an increase in apoptotis (Bax-to-Bcl-2 ratio and terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling positive cells) associated with an enhancement of CaMKII activity with respect to age-matched controls (phosphorylated-CaMKII, 98.7 ± 14.1 above control). Similar results were observed in 4-mo-ol...