Volume Overload-induced Hypertrophy Research Articles

Altered Cellular Protein Quality Control System Modulates Cardiomyocyte Function in Volume Overload-Induced Hypertrophy.

Volume-induced hypertrophy is one of the risk factors for cardiac morbidity and mortality. In addition, mechanical and metabolic dysfunction, aging, and cellular redox balance are also contributing factors to the disease progression. In this study, we used volume overload (VO), which was induced by an aortocaval fistula in 2-month-old male Wistar rats, and sham-operated animals served as control. Functional parameters were measured by transthoracic echocardiography at termination 4- or 8-months after VO. The animals showed hypertrophic remodeling that was accompanied by mechanical dysfunction and increased cardiomyocyte stiffness. These alterations were reversible upon treatment with glutathione. Cardiomyocyte dysfunction was associated with elevated oxidative stress markers with unchanged inflammatory signaling pathways. In addition, we observed altered phosphorylation status of small heat shock proteins 27 and 70 and diminished protease expression caspases 3 compared to the matched control group, indicating an impaired protein quality control system. Such alterations might be attributed to the increased oxidative stress as anticipated from the enhanced titin oxidation, ubiquitination, and the elevation in oxidative stress markers. Our study showed an early pathological response to VO, which manifests in cardiomyocyte mechanical dysfunction and dysregulated signaling pathways associated with enhanced oxidative stress and an impaired protein quality control system.

Regulation of L-type inward calcium channel activity by captopril and angiotensin II via the phosphatidyl inositol 3-kinase pathway in cardiomyocytes from volume-overload hypertrophied rat hearts

Heart failure can be caused by pro-hypertrophic humoral factors such as angiotensin II (Ang II), which regulates protein kinase activities. The intermingled responses of these kinases lead to the early compensated cardiac hypertrophy, but later to the uncompensated phase of heart failure. We have shown that although beneficial, cardiac hypertrophy is associated with modifications in ion channels that are mainly mediated through mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI3K) activation. This study evaluates the control of L-type Ca(2+) current (I(Ca,L)) by the Ang II/PI3K pathway in hypertrophied ventricular myocytes from volume-overload rats using the perforated patch-clamp technique. To assess activation of the I(Ca,L) in cardiomyocytes, voltages of 350 ms in 10 mV increments from a holding potential of -85 mV were applied to cardiocytes, with a pre-pulse to -45 mV for 300 ms. Volume overload-induced hypertrophy reduces I(Ca,L), whereas addition of Ang II alleviates the hypertrophic-induced decrease in a PI3K-dependent manner. Acute administration of Ang II (10(-6) mol/L) to normal adult cardiomyocytes had no effect; however, captopril reduced their basal I(Ca,L). In parallel, captopril regressed the hypertrophy and inverted the Ang II effect on I(Ca,L) seemingly through a PI3K upstream effector. Thus, it seems that regression of cardiac hypertrophy by captopril improved I(Ca,L) partly through PI3K.

Estrogen improves TIMP-MMP balance and collagen distribution in volume-overloaded hearts of ovariectomized females

Our previous studies demonstrate that 17beta-estradiol limits chronic volume overload-induced hypertrophy and improves heart function in ovariectomized rats. One possible cardioprotective mechanism involves the interaction between estrogen, estrogen receptors, and proteins of the extracellular matrix (ECM). The impact of estrogen deficiency and replacement on left ventricular (LV) hypertrophy and ECM protein expression was studied using five female rat groups: intact sham-operated, ovariectomized sham-operated, intact with volume overload, ovariectomized with volume overload, and ovariectomized with volume overload treated with estrogen. After 8 wk, LV protein extracts were evaluated by Western blot analysis for matrix metalloproteinase-2 (MMP-2) and MMP-9, MT1-MMP, tissue inhibitors of MMPs (TIMP)-1, TIMP-2, TIMP-3 and TIMP-4, collagens type I and III, and estrogen receptor alpha and beta expression. MMP proteolytic activity was assessed by zymography. All volume-overloaded groups exhibited LV hypertrophy, which was associated with a loss of interstitial collagen and perivascular fibrosis. After 8 wk of volume overload, 70% of ovariectomized rats developed heart failure, in contrast to only one intact rat. A downregulation of MMP-2, estrogen receptor-alpha (ERalpha), and ERbeta, and upregulation of MMP-9 and MT1-MMP were found in the volume-overloaded hearts of ovariectomized rats. Estrogen treatment improved TIMP-2/MMP-2 and TIMP-1/MMP-9 protein balance, restored ERalpha expression, and prevented MMP-9 activation, perivascular collagen accumulation and development of heart failure. However, estrogen did not fully restore ERbeta expression and did not prevent the increase of MMP-9 expression or loss of interstitial collagen. These results support that estrogen limits undesirable ECM remodeling and LV dilation, in part, through modulation of ECM protein expression in volume-overloaded hearts of ovariectomized rats.

Increased cardiac sympathetic activity and insulin-like growth factor-I formation are associated with physiological hypertrophy in athletes.

Physiological hypertrophy represents the adaptive changes of the heart required for supporting the increased hemodynamic load in regularly trained healthy subjects. Mechanisms responsible for the athlete's hypertrophy still remain unknown. In 15 trained competitive soccer players and in 15 healthy men not engaged in sporting activities (sedentary control subjects) of equivalent age, we investigated the relationship among cardiac growth factor formation, cardiac sympathetic activity, and left ventricular morphology and function. Cardiac formation of insulin-like growth factor (IGF)-I, endothelin (ET)-1, big ET-1, and angiotensin (Ang) II was investigated at rest by measuring artery-coronary sinus concentration gradients. Cardiac sympathetic activity was studied by [(3)H]norepinephrine (NE) kinetics. Cardiac IGF-I, but not ET-1, big ET-1, and Ang II, formation was higher in athletes than in control subjects (P<0.01). NE levels in arterial and peripheral venous blood did not differ between groups. In contrast, coronary sinus NE concentration was higher in athletes than in control subjects (P<0.01). Cardiac, but not total systemic, NE spillover was also increased in athletes (P<0.01), whereas cardiac [(3)H]NE reuptake and clearance were not different. Echocardiographic modifications indicated a volume overload-induced hypertrophy associated with increased myocardial contractility. Multivariate stepwise analysis selected left ventricular mass index as the most predictive independent variable for cardiac IGF-I formation and velocity of circumferential fiber shortening for cardiac NE spillover. In conclusion, increased cardiac IGF-I formation and enhanced sympathetic activity selectively confined to the heart appear to be responsible for the physiological hypertrophy in athletes performing predominantly isotonic exercise.

Altered Production of Endothelin-1 in the Hypertrophied Rat Heart

Although endothelin-1 (ET-1) has been shown to have potent hypertrophic effects in cultured cardiac myocytes, there is no evidence that the production of ET-1 is altered in the hypertrophied heart in vivo. We investigated mRNA and peptide levels of ET-1 in the rat heart hypertrophied due to pressure or volume overload. One week after surgery of abdominal aortic banding (AB) or aortic valve regurgitation (AR; the aortic valve was destroyed by a polyethylene catheter), the rats were sacrificed. Control sham-operated rats were also studied (AB-sham and AR-sham). The left ventricular (LV) weight to body weight ratio was significantly higher in AB rats than in AB-sham rats. It was also significantly higher in AR rats than in AR-sham rats. Therefore, AB rats and AR rats developed LV hypertrophy due to pressure and volume overload, respectively. The expression of ET-1 mRNA in the LV was markedly higher in AB rats than in AB-sham rats. The peptide level of ET-1 was also significantly higher in the LV of AB rats than in that of AB-sham rats. However, the expression of ET-1 mRNA in the LV of AR rats was similar to that of AR-sham rats. The present findings suggest that the production of ET-1 in the heart differs between pressure and volume overload-induced hypertrophy in rats.

Non-coordinate expression of collagen mRNAs during carbon monoxide-induced cardiac hypertrophy.

Collagen gene expression during volume overload-induced cardiac hypertrophy was investigated in adult male rats. Hypertrophy of the left ventricle (22%) and right ventricle (37%) occurred following 27 days continuous exposure to 700 ppm carbon monoxide; hematocrit increased nearly 47%. To examine potential cellular and molecular control of restructuring in the heart, we investigated the expression of two specific procollagen mRNAs for collagen types which have different structural-functional roles [Type I (alpha-1) & Type IV]. Type I (interstitial) mRNA levels increased at least 100% relative to controls within 3 days of initial exposure to 700 ppm CO, then declined afterwards; type IV (basement membrane) mRNA levels increased more modestly at first, and increased further afterwards. The ratio of type I/type IV RNA's also increased initially, then later declined, with the greatest differences in the relative responses of type I and IV mRNAs seen in the right ventricle. These data suggest that types I and IV collagen mRNA expression is not coordinately expressed during this type of volume overload-induced hypertrophy in rat heart.