Chronic Hypobaric Hypoxia Induces Right Ventricular Hypertrophy and Apoptosis in Rats: Therapeutic Potential of Nanocurcumin in Improving Adaptation

Abstract

Nehra, Sarita, Varun Bhardwaj, Santosh Kar, and Deepika Saraswat. Chronic hypobaric hypoxia induces right ventricular hypertrophy and apoptosis in rats: therapeutic potential of nanocurcumin in improving adaptation. High Alt Med Biol. 17:342-352, 2016.-a sustained work load on the right heart on ascent to high altitudes promotes right ventricular hypertrophy (RVH), which eventually undergoes decompensation and promotes pathological damage. However, the exact set of events leading to damage remains unidentified. Curcumin is a natural antioxidant and antihypertrophic agent, but it has poor biostability. Nanotized curcumin (nanocurcumin) has emerged as a promising agent with improved biostability while retaining the therapeutic properties of curcumin. The present study aimed at analyzing the therapeutic properties of nanocurcumin in ameliorating cardiac damage due to chronic hypobaric hypoxia (HH)-induced RVH in comparison to curcumin. Sprague-Dawley rats exposed to HH (25,000 feet, effective oxygen fraction in air [FO] ∼0.08, temperature 28°C ± 1°C, relative humidity 55% ± 2% for 3, 7, 14, and 21 days) developed RVH with increased interstitial collagen content, Fulton's index, and cardiomyocyte cross-sectional area while upregulating atrial natriuretic peptide. Tissue damage due to apoptotic cell death was evident by cytochrome-c/caspase-3 activation and TUNEL assay. Concomitant modulation of cyclic guanosine monophosphate (cGMP)/cGK-1, calmodulin-dependent protein kinase II (CaMkinase II), and intracellular calcium levels with increased free radical-induced damage and lipid peroxidation further contributed to the right heart pathology. Nanocurcumin supplementation decreased HH-induced RVH and apoptosis while modulating cardiac cGMP/cGK-1 signaling, and maintaining CaMkinase II, intracellular calcium levels and redox status better than curcumin. Nanocurcumin-mediated antiapoptotic effects might have benefited residents and sojourners at high altitude in preventing hypoxic cardiac damage.

Oxidative Stress, Kinase Activity and Inflammatory Implications in Right Ventricular Hypertrophy and Heart Failure under Hypobaric Hypoxia

“…Several studies have described that in different PH models, the inflammatory molecule IL-6 is increased both in plasma and RV tissue, which could be involved in cardiac function and morphology [36]. This is supported by a study by Nehra et al [14] in rats with RVH induced by hypobaric hypoxia (7620 m) showing an increase in circulating levels of TNF-α and IL-6, and these molecules were associated with a decompensated transition to RHF. Moreover, a recent study in mice with transverse aortic constriction shows new insight into hypoxia-induced mitogenic factor (HIMF), a cytokine-like protein that could induce cardiac hypertrophy, fibrosis and myofibroblast differentiation through IL-6 [97], which results in an interesting pathway to be analyzed in the transition to HF under this particular condition.…”

“…Additionally, the activation of molecular pathways and morphological changes, such as uncoupled endothelial nitric oxide synthase (eNOS), pro-inflammatory cytokines such as interleukin 1 and 6 (IL-1 and IL-6), and oxidative stress, among others, lead to pulmonary arterial remodeling and ultimately definitive pulmonary hypertension (PH) [11,12]. Thus, the principal consequence of HAPH is pressure overload (PO)-induced right ventricular hypertrophy (RVH) in the long term [13,14].…”

Transcriptomic profiles reveal differences between the right and left ventricle in normoxia and hypoxia

“…The rat model of chronic hypoxia employed in this study is a reversible model of RV hypertrophy that occurs prior to decompensated RV failure (Nehra, Bhardwaj, Kar, & Saraswat, ). Thus, our findings reflect what is observed in the nonfailing RV.…”

Nanocurcumin–pyrroloquinoline formulation prevents hypertrophy–induced pathological damage by relieving mitochondrial stress in cardiomyocytes under hypoxic conditions

“…Morphometry analysis of right ventricular hypertrophy (RVH) was performed by analyzing Fulton’s index (RV/LV+S and RV/BW) and histopathological assessment via Masson’s trichrome staining as previously described. 22 Circulating levels of atrial natriuretic factor (ANF) (ab108797, Abcam, Cambridge, UK) and brain natriuretic peptide (BNP) (ab108816, Abcam) were estimated as markers of cardiac hypertrophy using commercially available ELISA kits; the assays were performed according to manufacturer’s instructions. Tissue distribution of ANF was examined as a marker of hypertrophy by immunohistochemistry, and changes in tissue-architecture were analyzed by immunofluorescence staining using α-actin/DAPI.…”

“…In this regard, we have previously shown that nanotized curcumin (NC) ameliorates hypoxia stress both in vitro and in vivo. 3 , 4 , 22 , 23 Hypoxic stress elicits multiple physiological damages on normal physiological functions. 24 Additionally, the normal functioning of cardiomyocytes critically relies upon an optimal oxygen supply.…”