Changes in cardiac mechanics with heat acclimation:  adrenergic signaling and SR-Ca regulatory proteins

The involvement of adrenergic signaling and sarcoplasmic calcium regulatory proteins in the development of heat acclimation-induced adaptations in cardiac mechanics was studied in heat-acclimated (34°C) rats for 2, 5, and 30 days (AC2, AC5, and AC30, respectively). Control (C) rats were held at 24 ± 1°C. Systolic pressure (LVP) and velocities of contraction (dP/d t/P) and relaxation (−dP/d t/P) were measured using a Langendorff system. For adrenergic signaling, β-adrenoreceptor (AR) density and affinity (Scatchard plots) and cardiac inotropic response to norepinephrine (10− 7 mM, ± 10− 6 mM propranolol) were measured. For the regulatory proteins, steady-state levels of Ca2+-ATPase and phospholamban (PLB) mRNAs and the encoded proteins Ca2+-ATPase [sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)] and PLB were measured using semiquantitative RT-PCR and Western immunoblotting, respectively. Both short (STHA; AC2 and AC5)- and long-term heat acclimation (LTHA; AC30) enhanced LVP. However, dP/d t ⋅ P and −dP/d t ⋅ P in STHA hearts resembled that of the controls, whereas on LTHA, both parameters decreased ( P< 0.05), implying decreased velocity of contraction and relaxation. β-AR density remained unchanged with their affinity markedly decreased ( P < 0.05). AR responsiveness, however, diminished in AC2 but was markedly enhanced on LTHA. During STHA, PLB and sarcoplasmic reticulum Ca2+-ATPase transcripts were upregulated with no change in the encoded proteins except for SERCA downregulation on AC5, leading to an increased PLB/SERCA ratio ( P < 0.05). This mismatched preacclimation lusitropic state on STHA and increased PLB/SERCA ratio was evident ( P < 0.05) due to downregulation of SERCA and upregulation of PLB. Our data fit a biphasic acclimation model in which desensitized adrenergic signaling is dominant during STHA, whereas on LTHA, the contractile machinery is influenced by altered expression of the calcium regulatory proteins leading to both augmented adrenergic inotropic response (via PLB elevation) and decreased velocity of relaxation. The sustained low thyroxin measured on LTHA causally associates with this response.

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Matching the Heart to Heat-Induced Circulatory Load: Heat-Acclimatory Responses

Physiology ◽

10.1152/nips.01453.2003 ◽

2003 ◽

Vol 18 (6) ◽

pp. 215-221 ◽

Cited By ~ 5

Author(s):

Michal Horowitz

Keyword(s):

Heart Rate ◽

Oxygen Demand ◽

Heat Acclimation ◽

Regulatory Proteins ◽

Contractile Apparatus ◽

Cardiac Efficiency ◽

Cross Tolerance ◽

Altered Expression ◽

Expression Of Genes ◽

Cardiac Adaptation

Heat acclimation enhances cardiac efficiency by increasing stroke volume and decreasing heart rate. These adaptations involve biochemical changes in the contractile apparatus, switched on by altered expression of genes coding contractile and calcium-regulatory proteins and partially mediated by persistent low thyroxine. Heat acclimation also produces cross-tolerance to oxygen deprivation, thus reinforcing cardiac adaptation to oxygen demand/supply mismatching via energy-sparing pathways.

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Heat acclimation induces changes in cardiac mechanical performance: the role of thyroid hormone

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1999.276.2.r550 ◽

1999 ◽

Vol 276 (2) ◽

pp. R550-R558 ◽

Cited By ~ 12

Author(s):

Eynan Mirit ◽

Aharon Palmon ◽

Yonathan Hasin ◽

Michal Horowitz

Keyword(s):

Drinking Water ◽

Mechanical Performance ◽

Systolic Pressure ◽

Heat Acclimation ◽

Rt Pcr ◽

Thyroxine Level ◽

Rat Hearts ◽

Langendorff Perfusion ◽

Steady State Levels

The involvement of reduced thyroxine level in the emergence of heat acclimation-induced negative lusitropic effect was examined. Experiments were carried out on 1) control rat hearts maintained at 24 ± 1°C (C); 2) rat hearts acclimated at 34°C for 1 mo (AC); 3) AC-euthyroid rat hearts, via administration of thyroxine in the drinking water (AT); and 4) hypothyroid rat hearts, maintained at 24 ± 1°C, via administration of thiouracil in the drinking water (CP). Systolic pressure and velocities of contraction (dP/d t ⋅ P) and relaxation (−dP/d t ⋅ P) were measured using the Langendorff perfusion system. The steady-state levels of Ca2+-ATPase and phospholamban mRNAs and the expression of the encoded proteins Ca2+-ATPase (SERCA) and phospholamban (PLB) were measured, using semi-quantitative RT-PCR and Western immunoblotting, respectively. Rat thyroxine levels were measured using RIA. Heat acclimation, which brought about a reduced thyroxine level, led to downregulation of Ca2+-ATPase mRNA expression and translation and upregulation of phospholamban mRNA and PLB. Consequently, the PLB-to-SERCA ratio (PLB/SERCA) of the AC hearts showed a significant increase. These changes, as well as the greater pressure generation and the reduced dP/d t ⋅ P and −dP/d t ⋅ P observed in AC hearts were blunted in the AT hearts. Our data suggest that sustained heat acclimation-induced low thyroxine level has a decisive effect on the contractile machinery of the AC heart. Elevated PLB/SERCA apparently explains the negative lusitropic effect observed in these hearts.

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Heat acclimation improves cardiac mechanics and metabolic performance during ischemia and reperfusion

Journal of Applied Physiology ◽

10.1152/jappl.1993.75.2.833 ◽

1993 ◽

Vol 75 (2) ◽

pp. 833-839 ◽

Cited By ~ 45

Author(s):

E. Levi ◽

A. Vivi ◽

Y. Hasin ◽

M. Tassini ◽

G. Navon ◽

...

Keyword(s):

Intracellular Ph ◽

Perfusion Pressure ◽

Diastolic Pressure ◽

Systolic Pressure ◽

Cardiac Mechanics ◽

Heat Acclimation ◽

Resonance Spectroscopy ◽

Ischemia And Reperfusion ◽

Beneficial Effects ◽

Metabolic Performance

Cardiac mechanics and metabolic performance were studied in isolated perfused hearts of heat-acclimated (AC) rats (at 34 degrees C for 1 mo) and their age-matched controls (C). Diastolic and systolic pressures, coronary flow, and the appearance of ischemic contracture (IC) were measured during progressive graded ischemia, total ischemia (TI), and reperfusion. ATP, phosphocreatine, and intracellular pH were measured during TI and reperfusion with the use of 31P-nuclear magnetic resonance spectroscopy. Systolic pressure was greater in AC hearts than in C hearts (P < 0.0001). During 50% of perfusion pressure 15 and 46% of AC and C hearts, respectively, showed IC (P < 0.001). During 25% of perfusion pressure 85% of the hearts in both groups developed IC. The onset of IC in AC hearts was delayed compared with in C hearts. On reperfusion 93 and 66% of AC and C hearts, respectively, resumed contraction. Recovery of diastolic pressure was 78 and 36% for the AC and C hearts, respectively (P < 0.05). During TI ATP declined by 0.94 and 1.20 mumol/min in AC and C hearts, respectively, resulting in 21 +/- 2.8% preservation of the ATP pool in AC hearts after 30 min of TI (P < 0.001). The AC group also showed a delayed decline in intracellular pH (P < 0.001). The data suggest beneficial effects of heat acclimation on the heart, which were exhibited by greater pressure generation and by the emergence of protecting features during ischemia and reperfusion, possibly via energy-sparing mechanisms.

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Altered Expression of Complement Regulatory Proteins CD35, CD46, CD55, and CD59 on Leukocyte Subsets in Individuals Suffering From Coronary Artery Disease

Frontiers in Immunology ◽

10.3389/fimmu.2019.02072 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 1

Author(s):

Nitesh Mishra ◽

Madhav Mohata ◽

Rajeev Narang ◽

R. Lakshmy ◽

Anjali Hazarika ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Regulatory Proteins ◽

Altered Expression ◽

Complement Regulatory Proteins ◽

Artery Disease

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Altered expression of inhibitory guanine nucleotide regulatory proteins (Gi-proteins) in experimental hepatocellular carcinoma

Journal of Cellular Physiology ◽

10.1002/(sici)1097-4652(199806)175:3<295::aid-jcp7>3.0.co;2-j ◽

1998 ◽

Vol 175 (3) ◽

pp. 295-304 ◽

Cited By ~ 16

Author(s):

Iain H. McKillop ◽

Yuping Wu ◽

Paul A. Cahill ◽

James V. Sitzmann

Keyword(s):

Hepatocellular Carcinoma ◽

Regulatory Proteins ◽

Guanine Nucleotide ◽

Altered Expression ◽

Guanine Nucleotide Regulatory Proteins ◽

Gi Proteins

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Chronic heat improves mechanical and metabolic response of trained rat heart on ischemia and reperfusion

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.272.5.h2085 ◽

1997 ◽

Vol 272 (5) ◽

pp. H2085-H2094 ◽

Cited By ~ 12

Author(s):

E. Levy ◽

Y. Hasin ◽

G. Navon ◽

M. Horowitz

Keyword(s):

Oxygen Consumption ◽

Intracellular Ph ◽

Cardiac Mechanics ◽

Heat Acclimation ◽

High Energy ◽

Rate Pressure Product ◽

Resonance Spectroscopy ◽

Ischemia And Reperfusion ◽

Swimming Training ◽

Significant Difference

Cardiac mechanics and metabolic performance were studied in isolated perfused hearts of rats subjected to a combined chronic stress of heat acclimation and swimming training (EXAC) or swimming training alone (EX). Diastolic (DP) and systolic pressures (SP), coronary flow (CF), and oxygen consumption were measured during normoperfusion (80 mmHg), and the appearance of ischemic contracture (IC), DP, and SP were measured during progressive graded ischemia, total ischemia (TI), and reperfusion insults. ATP, phosphocreatine, and intracellular pH were measured during TI and reperfusion with 31P nuclear magnetic resonance spectroscopy. During normoperfusion, SP and cardiac efficiency (derived from rate-pressure product-oxygen consumption relationships) were the highest in the 2-mo EXAC hearts (P < 0.0001). During progressive graded ischemia, the development of IC (percentage of total hearts) was similar in both EXAC and EX hearts; the only significant difference was confined to the 1- vs. 2-mo groups. The onset of IC was delayed in the EXAC hearts and, on reperfusion, recovery, particularly of DP, was significantly improved in the latter. After TI, EXAC hearts retained 30% of the ATP pool and there was a delayed decline in intracellular pH. On reperfusion, these hearts also displayed improved ATP and phosphocreatine recovery, the 2-mo EXAC heart demonstrating significantly faster high-energy phosphate salvage, improved diastolic function, and pulse pressure recovery. The data attest to the beneficial effects of heat acclimation on cardiac mechanics of trained rats during normoperfusion and cardiac protection on ischemia and reperfusion. Possibly, energy sparing, lesser acidosis, and shorter duration of IC on ischemia and improved energy salvage on reperfusion contribute synergistically to this potent beneficial effect.

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Daily exercise-induced cardioprotection is associated with changes in calcium regulatory proteins in hypertensive rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00873.2004 ◽

2005 ◽

Vol 288 (2) ◽

pp. H532-H540 ◽

Cited By ~ 32

Author(s):

Heidi L. Collins ◽

Alfred M. Loka ◽

Stephen E. DiCarlo

Keyword(s):

Protein Expression ◽

Epidemiological Data ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Regulatory Proteins ◽

Hypertensive Rats ◽

Daily Exercise ◽

Plasmic Reticulum ◽

Exercise Induced ◽

Prevention Approach

Epidemiological data document that regular exercise protects against the morbidity and mortality associated with ischemic heart disease. Therefore, we tested the hypothesis that daily exercise (DE) increases the ventricular arrhythmia threshold (VAT) induced by coronary artery occlusion and alters the expression of calcium regulatory proteins. The VAT was defined as the time from coronary occlusion to sustained ventricular tachycardia resulting in a reduction in arterial pressure. To test this hypothesis, we recorded the VAT in conscious sedentary normotensive, sedentary hypertensive, and DE hypertensive rats, and we associated these thresholds with the protein expression of the L-type calcium channel, Na+/Ca2+ exchanger, phospholamban, and sarco(endo)plasmic reticulum Ca2+-ATPase. Results document a significantly reduced time to ventricular arrhythmias (sedentary hypertensive, 3.7 ± 0.3 min vs. sedentary normotensive, 4.8 ± 0.3 min), an increased Na+/Ca2+ exchanger protein expression (47%), and a decreased phospholamban protein expression (−34%) in conscious hypertensive rats. DE increased the VAT (5.9 ± 0.2 min), decreased the protein expression of the Na+/Ca2+ exchanger, and normalized the protein expression of phospholamban in the hypertensive rats. Thus DE may be a primary prevention approach for reducing the incidence of arrhythmias by altering calcium regulatory proteins in hypertensive rats.

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Expression of regulatory proteins and proliferative activity in relation to phenotypic characteristics of upper urothelial carcinoma

Vojnosanitetski pregled ◽

10.2298/vsp1107567d ◽

2011 ◽

Vol 68 (7) ◽

pp. 567-574 ◽

Cited By ~ 3

Author(s):

Zana Dolicanin ◽

Ljubinka Jankovic-Velickovic ◽

Biljana Djordjevic ◽

Milan Visnjic ◽

Ivana Pesic ◽

...

Keyword(s):

Cell Cycle ◽

Molecular Markers ◽

Urothelial Carcinoma ◽

Cyclin D1 ◽

Regulatory Proteins ◽

High Expression ◽

Phenotypic Characteristics ◽

Ki 67 ◽

Altered Expression ◽

Her 2

Background/Aim. Deregulation of the normal cell cycle is common in upper urothelial carcinoma (UUC). The aim of this study was to investigate the expression of regulatory proteins of the cell cycle (p53, p16, cyclin D1, HER-2) and proliferative Ki-67 activity in UUC, and to determine their interaction and influence on the phenotypic characteristics of UUC. Methods. In 44 patients with UUC, histopathological and immunohistochemical analyses (p53, p16, cyclin D1, HER-2, and Ki-67) of tumors were done. Results. Overexpression/ altered expression of p53, p16, cyclin D1 or HER-2 was detected in 20%, 57%, 64%, and 57% of tumors, respectively. Eleven (25%) UUC had a high proliferative Ki-67 index. Forty patients (91%) had at least one marker altered, while four (9%) tumors had a wild-type status. Analysis of relationship between expressions of molecular markers showed that only high expression of p53 was significantly associated with altered p16 activity (p < 0.05). High Ki-67 index was associated with the high stage (p < 0.005), solid growth (p < 0.01), high grade (p < 0.05), and multifocality p < 0.05) of UUC, while high expression of p53 was associated with the solid growth (p < 0.05). In regression models that included all molecular markers and phenotypic characteristics, only Ki-67 correlated with the growth (p < 0.0001), stage (p < 0.01), grade (p < 0.05) and multifocality (p < 0.05) of UUC; Ki-67 and HER-2 expression correlated with the lymphovascular invasion (p < 0.05). Conclusions. This investigation showed that only negative regulatory proteins of the cell cycle, p53 and p16, were significantly associated in UUC, while proliferative marker Ki-67 was in relation to the key phenotypic characteristics of UUC in the best way.

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Altered Expression of G1 Regulatory Proteins in Human Soft Tissue Sarcomas

Archives of Pathology & Laboratory Medicine ◽

10.5858/2002-126-0567-aeogrp ◽

2002 ◽

Vol 126 (5) ◽

pp. 567-573 ◽

Cited By ~ 1

Author(s):

Jinyoung Yoo ◽

Sonya Y. Park ◽

Seok Jin Kang ◽

Sang In Shim ◽

Byung Kee Kim

Keyword(s):

Cell Cycle ◽

Soft Tissue ◽

Cyclin D1 ◽

Soft Tissue Sarcomas ◽

Tumor Grade ◽

Regulatory Proteins ◽

Nuclear Accumulation ◽

Cyclin D ◽

P53 Pathway ◽

Altered Expression

Abstract Context.—Soft tissue sarcomas constitute a heterogeneous group of tumors for which tumorigenesis is not fully understood. Altered cell-cycle regulation may underlie the development and/or progression of human malignancies. However, data concerning the occurrence of cell-cycle aberrations in soft tissue sarcomas are very limited. Objectives.—To detect the abnormal features of cell-cycle regulatory proteins in soft tissue sarcomas and to determine the potential role of these proteins in clinical behavior. Design.—The p53 and Rb–cyclin D pathways were investigated by immunohistochemical studies of p53, mdm2, pRb, p16, cyclin D1, and cdk4 proteins, respectively. Results.—Of the 67 sarcomas analyzed, nuclear accumulation of p53 was detected in 25 samples (37%), and overexpression of mdm2 was found in 16 samples (24%). Both p53 and mdm2 expression correlated with tumor grade. Abnormalities involving the Rb–cyclin D pathway were identified in all of the tumors by the altered expression of either pRb (72%) or p16 (94%). Fourteen (21%) and 64 (96%) cases demonstrated cyclin D1 or cdk4 expression, respectively. Overexpression of cyclin D1 showed an association with pRb and p53. There was no correlation between pRb, p16, cyclin D1, or cdk4 and tumor grade or relapse. Conclusion.—Disturbance in the cell-cycle regulatory system involving the p53 pathway and the Rb–cyclin D pathway is relatively frequent in soft tissue sarcomas and may be a contributing factor in the tumorigenesis of these tumors. The alterations in the Rb–cyclin D pathway probably constitute an early event, whereas the abnormalities in the p53 pathway seem to be involved in tumor progression. It is noteworthy that cyclin D1 may play a key role in linking both pathways.

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