Mitochondrial Volume Regulation and Swelling Mechanisms in Cardiomyocytes.

Mitochondrion, known as the "powerhouse" of the cell, regulates ion homeostasis, redox state, cell proliferation and differentiation, and lipid synthesis. The inner mitochondrial membrane (IMM) controls mitochondrial metabolism and function. It possesses high levels of proteins that account for ~70% of the membrane mass and are involved in the electron transport chain, oxidative phosphorylation, energy transfer, and ion transport, among others. The mitochondrial matrix volume plays a crucial role in IMM remodeling. Several ion transport mechanisms, particularly K+ and Ca2+, regulate matrix volume. Small increases in matrix volume through IMM alterations can activate mitochondrial respiration, whereas excessive swelling can impair the IMM topology and initiates mitochondria-mediated cell death. The opening of mitochondrial permeability transition pores, the well-characterized phenomenon with unknown molecular identity, in low- and high-conductance modes are involved in physiological and pathological increases of matrix volume. Despite extensive studies, the precise mechanisms underlying changes in matrix volume and IMM structural remodeling in response to energy and oxidative stressors remain unknown. This review summarizes and discusses previous studies on the mechanisms involved in regulating mitochondrial matrix volume, IMM remodeling, and the crosstalk between these processes.

Mitochondrial angiotensin receptors and cardioprotective pathways.

A growing body of data provides strong evidence that intracellular angiotensin II (ANG II) plays an important role in mammalian cell function and is involved in the pathogenesis of human diseases such as hypertension, diabetes, inflammation, fibrosis, arrhythmias, and kidney disease, among others. Recent studies also suggest that intracellular ANG II exerts protective effects in cells during high extracellular levels of the hormone or during chronic stimulation of the local tissue renin-angiotensin system (RAS). Notably, the intracellular RAS (iRAS) described in neurons, fibroblasts, renal cells, and cardiomyocytes provided new insights into regulatory mechanisms mediated by intracellular ANG II type 1 (AT1Rs) and 2 (AT2Rs) receptors, particularly, in mitochondria and nucleus. For instance, ANG II through nuclear AT1Rs promotes protective mechanisms by stimulating the AT2R signaling cascade, which involves mitochondrial AT2Rs and Mas receptors. The stimulation of nuclear ANG II receptors enhances mitochondrial biogenesis through peroxisome proliferator-activated receptor-γ coactivator-1α and increases sirtuins activity, thus protecting the cell against oxidative stress. Recent studies in ANG II-induced preconditioning suggest that plasma membrane AT2R stimulation exerts protective effects against cardiac ischemia-reperfusion by modulating mitochondrial AT1R and AT2R signaling. These studies indicate that iRAS promotes the protection of cells through nuclear AT1R signaling, which, in turn, promotes AT2R-dependent processes in mitochondria. Thus, despite abundant data on the deleterious effects of intracellular ANG II, a growing body of studies also supports a protective role for iRAS that could be of relevance to developing new therapeutic strategies. This review summarizes and discusses previous studies on the role of iRAS, particularly emphasizing the protective and counterbalancing actions of iRAS, mitochondrial ANG II receptors, and their implications for organ protection.

Critical role of angiotensin II type 2 receptors in the control of mitochondrial and cardiac function in angiotensin II-preconditioned rat hearts.

Angiotensin II preconditioning (APC) involves an angiotensin II type 1 receptor (AT1-R)-dependent translocation of PKCε and survival kinases to the mitochondria leading to cardioprotection after ischemia-reperfusion (IR). However, the role that mitochondrial AT1-Rs and angiotensin II type 2 receptors (AT2-Rs) play in APC is unknown. We investigated whether pretreatment of Langendorff-perfused rat hearts with losartan (L, AT1-R blocker), PD 123,319 (PD, AT2-R blocker), or their combination (L + PD) affects mitochondrial AT1-R, AT2-R, PKCε, PKCδ, Akt, PKG-1, MAPKs (ERK1/2, JNK, p38), mitochondrial respiration, cardiac function, and infarct size (IS). The results indicate that expression of mitochondrial AT1-Rs and AT2-Rs were enhanced by APC 1.91-fold and 2.32-fold, respectively. Expression of AT2-R was abolished by PD but not by L, whereas the AT1-R levels were abrogated by both blockers. The AT1-R response profile to L and PD was also shared by PKCε, Akt, MAPKs, and PKG-1, but not by PKCδ. A marked increase in state 3 (1.84-fold) and respiratory control index (1.86-fold) of mitochondria was observed with PD regardless of L treatment. PD also enhanced the post-ischemic recovery of rate pressure product (RPP) by 74% (p < 0.05) compared with APC alone. Losartan, however, inhibited the (RPP) by 44% (p < 0.05) before IR and reduced the APC-induced increase of post-ischemic cardiac recovery by 73% (p < 0.05). Finally, L enhanced the reduction of IS by APC through a PD-sensitive mechanism. These findings suggest that APC upregulates angiotensin II receptors in mitochondria and that AT2-Rs are cardioprotective through their permissive action on AT1-R signaling and the suppression of cardiac function.

Angiotensin II-preconditioning is associated with increased PKCε/PKCδ ratio and prosurvival kinases in mitochondria.

Angiotensin II-preconditioning (APC) has been shown to reproduce the cardioprotective effects of ischaemic preconditioning (IPC), however, the molecular mechanisms mediating the effects of APC remain unknown. In this study, Langendorff-perfused rat hearts were subjected to IPC, APC or both (IPC/APC) followed by ischaemia-reperfusion (IR), to determine translocation of PKCε, PKCδ, Akt, Erk1/2, JNK, p38 MAPK and GSK-3ß to mitochondria as an indicator of activation of the protein kinases. In agreement with previous observations, IPC, APC and IPC/APC increased the recovery of left ventricular developed pressure (LVDP), reduced infarct size (IS) and lactate dehydrogenase (LDH) release, compared to controls. These effects were associated with increased mitochondrial PKCε/PKCδ ratio, Akt, Erk1/2, JNK, and inhibition of permeability transition pore (mPTP) opening. Chelerythrine, a pan-PKC inhibitor, abolished the enhancements of PKCε but increased PKCδ expression, and inhibited Akt, Erk1/2, and JNK protein levels. The drug had no effect on the APC- and IPC/APC-induced cardioprotection as previously reported, but enhanced the post-ischaemic LVDP in controls. Losartan, an angiotensin II type 1 receptor (AT1-R) blocker, abolished the APC-stimulated increase of LVDP and reduced PKCε, Akt, Erk1/2, JNK, and p38. Both drugs reduced ischaemic contracture and LDH release, and abolished the inhibition of mPTP by the preconditioning. Chelerythrine also prevented the reduction of IS by APC and IPC/APC. These results suggest that the cardioprotection induced by APC and IPC/APC involves an AT1-R-dependent translocation of PKCε and survival kinases to the mitochondria leading to mPTP inhibition. In chelerythrine-treated hearts, however, alternate mechanisms appear to maintain cardiac function.

The Role of SIRT3 in Mediating Cardioprotective Effects of RAS Inhibition on Cardiac Ischemia-Reperfusion.

Cardiac ischemia-reperfusion stimulates the renin-angiotensin system (RAS) associated with elevated levels of circulating angiotensin II. Numerous studies demonstrate that the antagonist for the angiotensin II type 1 receptor, losartan improves cardiac function in animal models of ischemia-reperfusion. Molecular mechanisms of the cardioprotective effects of RAS inhibitors on cardiac ischemia-reperfusion remain poorly understood, and are not associated with the anti-hypertensive action of these drugs. This Commentary focuses on the study published in the Journal of Pharmacy and Pharmaceutical Sciences, 2015, 18:112-123, that elucidates the role of SIRT3 in the cardioprotective action of losartan against ischemic-reperfusion injury. We provide comprehensive discussion of the role of mitochondria in the cardioprotective effects of losartan through SIRT3. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Coronary levels of angiotensin-II and endothelin-I in diabetic patients with and without coronary artery disease.

Two groups of patients were studied to find out the levels of angiotensin-II and endothelin-I in the coronary and peripheral circulation. Group A consisted of eight patients with diabetes mellitus type 2 and coronary artery disease; and Group B with diabetes mellitus without coronary artery disease. Significant differences were found between Group A and B in the levels of both peptides peripherally and intracoronary. This shows the importance of these peptides in the origin of coronary artery disease and progression of the disease in diabetics with coronary artery disease.

Celiac trunk and branches dissection due to energy drink consumption and heavy resistance exercise: case report and review of literature.

Higher doses and consumption of energy drinks leads to cardiovascular effects and potential consequences. Principal components found in energy drinks such as caffeine, guarana and taurine has been related to dilatation, aneurysm formation, dissection and ruptures. There is no evidence showing an integration of these components and its effects in endothelium and aortic walls due to higher levels of pressure during exercises. We report a case of a 44 years male with celiac trunk and branches dissection due to long-term consumption of energy drinks and intense exercise routine. Our proposition relates cell and vessel walls alterations including elasticity in endothelial wall due to higher blood pressure, resistance by intense exercise routine and long-term consumption of energy drinks.

Metabolic Changes After Roux-N-Y Bariatric Surgery In Hispanics.

The objective was to describe the metabolic outcomes 12 months after bariatric surgery (Roux-N-Y) in morbidly obese Hispanic patients, and evaluate the correlation between weight loss and the observed changes. Medical records from a hundred-and-two Hispanic obese patients who underwent bariatric surgery were identified at the University of Puerto Rico (UPR) Hospital. The following variables were obtained before and 12 months after surgery: Body Mass Index (BMI), body weight, total cholesterol (TC), triglycerides, high density lipoprotein (HDL), low density lipoprotein (LDL), and fasting blood sugar (FBS). Ninety-seven percent of patients underwent Roux-N-Y surgery; 79.4% were females and 44% were diabetics. We observed statistically significant reductions (p < 0.05) 12 months after surgery in: BMI -14.3 (± 6.2) kg/m2, weight -86.1 (± 34.4) Ibs, TC -17.9 (± 32.4) mg/dL, triglycerides -28.7(± 40.6) mg/dL, LDL-15.4 (± 30.6) mg/dL, and FBS -11.3 (± 23.5) mg/dL. HDL, instead increased +5.22 (± 12.9) mg/dL (p < 0.0006). Gastric bypass surgery of the Roux-N-Y significantly improves the lipid profile and FBS levels in obese Hispanic patients. The poor correlation factor between weight loss and these variables suggests that other mechanisms, independent from weight loss, are responsible for these changes.

Mitochondria-targeted ROS scavenger improves post-ischemic recovery of cardiac function and attenuates mitochondrial abnormalities in aged rats.

Mitochondria-generated reactive oxygen species (ROS) play a crucial role in the pathogenesis of aging and age-associated diseases. In this study, we evaluated the effects of XJB-5-131 (XJB), a mitochondria-targeted ROS and electron scavenger, on cardiac resistance to ischemia-reperfusion (IR)-induced oxidative stress in aged rats. Male adult (5-month old, n=17) and aged (29-month old, n=19) Fischer Brown Norway (F344/BN) rats were randomly assigned to the following groups: adult (A), adult+XJB (AX), aged (O), and aged+XJB (OX). XJB was administered 3 times per week (3mg/kg body weight, IP) for four weeks. At the end of the treatment period, cardiac function was continuously monitored in excised hearts using the Langendorff technique for 30 min, followed by 20 min of global ischemia, and 60-min reperfusion. XJB improved post-ischemic recovery of aged hearts, as evidenced by greater left ventricular developed-pressures and rate-pressure products than the untreated, aged-matched group. The state 3 respiration rates at complexes I, II and IV of mitochondria isolated from XJB-treated aged hearts were 57% (P<0.05), 25% (P<0.05) and 28% (P<0.05), respectively, higher than controls. Ca(2+)-induced swelling, an indicator of permeability transition pore opening, was reduced in the mitochondria of XJB-treated aged rats. In addition, XJB significantly attenuated the H2O2-induced depolarization of the mitochondrial inner membrane as well as the total and mitochondrial ROS levels in cultured cardiomyocytes. This study underlines the importance of mitochondrial ROS in aging-induced cardiac dysfunction and suggests that targeting mitochondrial ROS may be an effective therapeutic approach to protect the aged heart against IR injury.

Angiotensin II and ischemic preconditioning synergize to improve mitochondrial function while showing additive effects on ventricular postischemic recovery.

Recent studies indicate that the cardioprotective effects of ischemic preconditioning (IPC) against sustained ischemia/reperfusion can be replicated by angiotensin II (Ang II). However, it is not clear whether IPC and Ang II-induced preconditioning (APC) act through similar mechanisms or synergize to enhance cardioprotection. In this study, Langendorff-perfused rat hearts were subjected to IPC, APC, or their combination (IPC/APC) followed by ischemia/reperfusion. IPC, and less potently APC, significantly increased the percent recoveries of the left ventricular developed pressure, the first derivative of developed pressure, and the rate pressure product compared with control. Furthermore, the postischemic recovery of the heart was significantly higher for IPC/APC compared with IPC or APC. The improvements in cardiac function by IPC, APC, and IPC/APC were associated with similar reductions in lactate dehydrogenase release and infarct size. However, a significant improvement in mitochondrial respiration was observed with IPC/APC. The postischemic recovery observed with APC and IPC/APC was inhibited by treatment with losartan, an Ang II type-1 receptor blocker, during the preconditioning phase but not by chelerythrine, a pan-PKC inhibitor. Both drugs, however, abolished the enhanced mitochondrial respiration by IPC/APC. Altogether, these results indicate that APC and IPC interact through mechanisms that enhance cardioprotection by affecting cardiac function and mitochondrial respiration.

Magnesium: the forgotten electrolyte.

UNLABELLED: Magnesium (Mg++), Potassium (K+) and Calcium (CA++) are important electrolytes in keeping a stable electrical status. The purpose of this study was to measure them in critically ill patients. METHODS: We evaluated the electrolytes in 28 consecutive patients. Eighteen were females and 10 males with mean age of 62 +/- 5 years. RESULTS: The admission diagnosis in 95% of the cases was congestive heart failure. Sixty-four percent of the patients had subnormal values of Mg++, 53% subnormal values of K+, and 28% subnormal values of CA++. Fourteen percent showed lower values of the three electrolytes and 35% only of Mg++ and K+ concomitantly. Twenty-eight percent showed prolonged QTC interval. All patients with prolonged QTC interval had low Mg++ and K+ levels. Twenty five percent of the patients showed atrial fibrillation, 25% ventricular tachycardia, and 3% junctional tachycardia. The ventricular tachycardia group had more electrolyte abnormalities than those with atrial fibrillation. None of the patients received Mg++ replacement during critical management while 50% received K+ replacement. CONCLUSION: This data shows physician overlook the Importance of Mg++ and K+ deficiency in critically ill patients.

Ethnicity and genetics are more important than diabetes mellitus and hypertension in producing cardiovascular events in patients with the metabolic syndrome: emphasis in the Puerto Rico population.

Metabolic syndrome is a cluster of risk factors for cardiovascular disease that affects an estimated 50 million Americans. The present article reviews the metabolic syndrome with respect to its definition, epidemiology, pathophysiology and management. A primary focus in research has been to elucidate the processes determined to cause insulin resistance, the fundamental mechanism underlying the metabolic syndrome. Namely, the incidence, component characteristics and complications of the metabolic syndrome in the island of Puerto Rico are described alongside the fact that the metabolic syndrome may be milder in Puerto Rico than in the mainland United States because it is characterized by less aggressive coronary disease and a relatively normal lipid profile. This suggests that the cardiovascular complications are more influenced by genetics and culture than diabetes mellitus and hypertension.

Heart tumors in Puerto Rico de novo atrial fibrillation as clinical presentation in a subgroup of patients.

OBJECTIVE: Primary cardiac tumors are rare neoplasms in humans, of which the most common is the atrial Myxoma. The objective of this study was to find the incidence of these tumors at the Heart Center of Puerto Rico and the Caribbean. METHODS: This study was approved by the Institutional Review Board of the Medical Sciences Campus University of Puerto Rico to review the records at the Heart Center of patients with heart tumors in the last 14 years. RESULTS: The sample consists of 55 patients (78.9% were females and 24.1% were male) with a median age of 52 years. Sixty-five percent of patients lived in rural areas. Clinical presentations included shortness of breath (43.1%), chest pain (37.9%), asymptomatic (25%), palpitations (20.7%), neurologic symptoms (10.3%) and dizziness (6.9%). Electrocardiographic findings included normal sinus rhythm (53.4%), non-specific ST-T changes (32.8%), sinus tachycardia (20.7%), left atrial enlargement (10.3%) and atrial fibrillation (8.6%). A subgroup presenting with atrial fibrillation prior to diagnosis had left atrial myxoma. The tumors found, in descending order of frequency are: left atrial myxoma, right atrial myxoma, papillary fibroelastoma, hamartoma, lipoma and rhabdomyoma. We found a correlation between large left atrial myxoma and atrial fibrillation. CONCLUSION: The most frequent heart tumor was atrial myxoma. The larger myxomas were associated with atrial fibrillation.

The Department of Physiology of the UPR-School of Medicine: history and contribution to the physiological sciences in Puerto Rico 1950-2010.

In 1949, the creation of the University of Puerto Rico-School of Medicine required the recruitment of a group of faculty with expertise in the physiological sciences. The assembled group established the foundation for the Department of Physiology in the fall of 1950. Since then, the Department has made important contributions to the School of Medicine, the Medical Sciences Campus, and the University of Puerto Rico. These contributions include among others, participation in the educational programs in medicine, dentistry, and the biomedical sciences, the generation of knowledge in science through research in different components of the physiological sciences, and the development of researchers and academicians, many of whom have eventually occupied key positions in the UPR system and the private sector. Through the involvement of key faculty in the development of the MBRS-SCORE and RCMI Programs, the Department has made significant contributions to the infrastructure of the Medical Sciences Campus. Recently, the Department faculty was instrumental in the formation of the Puerto Rico Physiological Society to help promote education and research in the physiological sciences in Puerto Rico. Sixty years after its creation, the Department of Physiology is stronger than ever, and looks to the future with optimism, based on our learned experiences and our capacity to adapt in response to the evolving needs of research and education.

Aliskiren improves left ventricular dysfunction and reduces cardiac dilation in Syrian cardiomyopathic hamsters.

OBJECTIVE: Chronic activation of the renin-angiotensin-aldosterone system is a major contributing factor to the pathogenesis and progression of cardiovascular and renal diseases. METHODS: To evaluate the role of renin-angiotensin-aldosterone system blockade with aliskiren, a direct renin inhibitor, in the development and progression of dilated cardiomyopathy in the Syrian cardiomyopathic hamster (SCH) model, we treated 1-month-old SCH with aliskiren (10 mg·kg·d) over a 4-month period. For comparative purposes, we also evaluated the effects of the angiotensin receptor blocker valsartan (10 mg·kg·d) and the combination of both drugs. Age-matched golden hamsters were used as controls. Left ventricular end-diastolic volume and end-systolic volume, ejection fraction, and diastolic function were determined by echocardiography. Systolic blood pressure (SBP) was also measured in the left femoral artery by sphygmomanometry. RESULTS: Results indicate that at 2 months of age, SBP is higher in SCH than in controls, and administration for 1 month of aliskiren, valsartan, or the combination of these drugs normalized SBP in SCH to a similar extent. In 5-month-old SCH, aliskiren improved ejection fraction (from 48.6% ± 5.8% to 69.4% ± 3.2%, n = 5, P < 0.05), left ventricular end-systolic volume (from 0.28 ± 0.06 to 0.10 ± 0.01 mL/100 g body weight), left ventricular end-diastolic volume (from 0.61 ± 0.05 to 0.34 ± 0.02 mL/100 g body weight), and normalized diastolic function (E:A ratio increases from 0.93 ± 0.13 to 1.70 ± 0.03, n = 5, P < 0.05). Similar results were observed with valsartan or the combination of aliskiren and valsartan. CONCLUSIONS: Our results indicate that in this animal model, aliskiren is as effective as valsartan, or the combination of both drugs, in improving diastolic function and in preventing the development of dilated cardiomyopathy. These findings suggest that aliskiren may be used as a monotherapy in heart failure management. Clinical studies, however, are needed to assess the effectiveness of this drug in patients with heart failure.

Metabolic syndrome among Puerto Ricans and other Hispanic populations.

Metabolic syndrome is a cluster of risk factors for cardiovascular disease that affects an estimated 50 million Americans. The present article reviews this syndrome with respect to its definition, epidemiology, pathophysiology, and management. A primary focus in research has been to elucidate the processes that have been determined to cause insulin resistance, the fundamental mechanism underlying metabolic syndrome; these processes are reviewed here along with the interplay of the syndrome with the renin-angiotensin system, circadian rhythm, and atherosclerosis. Lifestyle changes promoting exercise and a healthy diet can reduce the incidence and prevent the progression of metabolic syndrome; however, refractory cases may warrant drug therapy. Recent emphasis has been placed on targeting obesity and insulin resistance as new therapeutic modalities are developed. In this manuscript, the incidence, component characteristics, and complications of metabolic syndrome in island-living Puerto Ricans and other Hispanic populations are described. The fact that island patients suffering from the syndrome tend to have less aggressive coronary disease and relatively normal lipid profile compared to their stateside counterparts is also discussed.

Chronic treatment with N-acetylcysteine improves cardiac function but does not prevent progression of cardiomyopathy in Syrian cardiomyopathic hamsters.

Oxidative stress has been postulated to contribute to the onset and development of heart failure (HF). The efficacy of antioxidant therapy in HF, however, remains controversial. This study evaluates the effect of the antioxidant N-acetylcysteine (NAC, 1 g/kg per day) on cardiovascular function in 2- and 6-month-old Bio-TO2 Syrian cardiomyopathic hamsters (SCH) after treatment for 1 month and 5 months with this drug. Endothelial function, systolic blood pressure (SBP), and echocardiographic parameters were evaluated. Age-matched F1-B golden hamsters were used as controls. One month of NAC administration significantly decreased SBP in 2-month-old SCH (n = 5, P < 0.001) without modifying echocardiographic values. Five-month treatment of cardiomyopathic animals with the antioxidant improved the acetylcholine-induced relaxation in aortic rings by 24% (E( Max) value from 45.8% ± 4% to 55.3% ± 2% n = 7, P < .05) but did not modify EC(50) values for the acetylcholine concentration-response curve. In addition, 5-month administration of NAC to SCH increased ejection fraction from 39% ± 4% to 57% ± 4% (n = 11, P < .001) and decreased left ventricular end-diastolic and end-systolic volumes (from 0.38 ± 0.04 mL/100 g body weight (BW) and 0.22 ± 0.03 mL/100 g BW, before, to 0.24 ± 0.04 mL/100 g BW and 0.12 ± 0.03 mL/100 g BW after treatment, P < .01). Cardiac output index also improved after 5 months of treatment, although it did not reach statistical significance. These results suggest that antioxidant therapy alone decreases ventricular dilatation and improves cardiovascular function in this animal model of dilated cardiomyopathy, but it does not prevent the appearance of HF.

Higher incidence of atrial fibrillation in the metabolic syndrome: a Hispanic population study.

UNLABELLED: The metabolic syndrome is probably one of the main medical problems in developing countries. Purpose of this investigation was to study the metabolic syndrome at the Puerto Rico and Caribbean Cardiovascular Center with emphasis on the cardiovascular complications. MATERIALS/METHODS: The medical charts in the last six years of the metabolic syndrome were evaluated at the PRCCC. RESULTS: One Hundred and Seventy-Three patients met the consensus criteria of the metabolic syndrome. The mean age was 60 years. Fifty-seven percent were males and 42% females. The mean body mass was 30 kg/m. The ejection fraction was subnormal (49 +/- 8%). The end systolic dimension of the left atrium was increased (45 +/- 10mm) when compared to normal. The incidence of atrial fibrillation was 16%. CONCLUSIONS: The metabolic syndrome in this sub-group of Hispanics, showed a higher incidence of atrial fibrillation without ventricular tachycardia. This is probably related to abnormal left ventricular and atrial function.

Expression of mitochondrial fusion-fission proteins during post-infarction remodeling: the effect of NHE-1 inhibition.

Studies on the role of mitochondrial fission/fusion (MFF) proteins in the heart have been initiated recently due to their biological significance in cell metabolism. We hypothesized that the expression of MFF proteins is affected by post-infarction remodeling and in vitro cardiomyocyte hypertrophy, and serves as a target for the Na(+)/H(+) exchanger 1 (NHE-1) inhibition. Post-infarction remodeling was induced in Sprague-Dawley rats by coronary artery ligation (CAL) while in vitro hypertrophy was induced in cardiomyocytes by phenylephrine (PE). Mitochondrial fission (Fis1, DRP1) and fusion (Mfn2, OPA1) proteins were analyzed in heart homogenates and cell lysates by Western blotting. Our results showed that 12 and 18 weeks after CAL, Fis1 increased by 80% (P < 0.01) and 31% (P < 0.05), and Mfn2 was reduced by 17% (P < 0.05) and 22% (P < 0.05), respectively. OPA1 was not changed at 12 weeks, although its expression decreased by 18% (P < 0.05) with 18 weeks of ligation. MFF proteins were also affected by PE-induced hypertrophy that was dependent on mitochondrial permeability transition pore opening and oxidative stress. The NHE-1-specific inhibitor EMD-87580 (EMD) attenuated changes in the expression of MFF proteins in both the models of hypertrophy. The effect of EMD was likely mediated, at least in part, through its direct action on mitochondria since Percoll-purified mitochondria and mitoplasts have been shown to contain NHE-1. Our study provides the first evidence linking cardiac hypertrophy with MFF proteins expression that was affected by NHE-1 inhibition, thus suggesting that MFF proteins might be a target for pharmacotherapy with anti-hypertrophic drugs.