Homocysteine and Hypertension in Diabetes: Does PPARγ Have a Regulatory Role?

Dysfunction of macro- and microvessels is a major cause of morbidity and mortality in patients with cardio-renovascular diseases such as atherosclerosis, hypertension, and diabetes. Renal failure and impairment of renal function due to vasoconstriction of the glomerular arteriole in diabetic nephropathy leads to renal volume retention and increase in plasma homocysteine level. Homocysteine, which is a nonprotein amino acid, at elevated levels is an independent cardio-renovascular risk factor. Homocysteine induces oxidative injury of vascular endothelial cells, involved in matrix remodeling through modulation of the matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) axis, and increased formation and accumulation of extracellular matrix protein, such as collagen. In heart this leads to increased endothelial-myocyte uncoupling resulting in diastolic dysfunction and hypertension. In the kidney, increased matrix accumulation in the glomerulus causes glomerulosclerosis resulting in hypofiltration, increased renal volume retention, and hypertension. PPARγ agonist reduces tissue homocysteine levels and is reported to ameliorate homocysteine-induced deleterious vascular effects in diabetes. This review, in light of current information, focuses on the beneficial effects of PPARγ agonist in homocysteine-associated hypertension and vascular remodeling in diabetes

Hydrogen sulphide mitigates homocysteine-induced apoptosis and matrix remodelling in mesangial cells through Akt/FOXO1 signalling cascade

Cellular damage and accumulation of extracellular matrix (ECM) protein in the glomerulo-interstitial space are the signatures of chronic kidney disease (CKD). Hyperhomocysteinemia (HHcy), a high level of homocysteine (Hcy) is associated with CKD and further contributes to kidney damage. Despite a large number of studies, the signalling mechanism of Hcy-mediated cellular damage and ECM remodelling in kidney remains inconclusive. Hcy metabolizes to produce hydrogen sulphide (H2S), and a number of studies have shown that H2S mitigates the adverse effect of HHcy in a variety of diseases involving several signalling molecules, including forkhead box O (FOXO) protein. FOXO is a group of transcription factor that includes FOXO1, which plays important roles in cell growth and proliferation. On the other hand, a cell survival factor, Akt regulates FOXO under normal condition. However, the involvement of Akt/FOXO1 pathway in Hcy-induced mesangial cell damage remains elusive, and whether H2S plays any protective roles has yet to be clearly defined. We treated mouse mesangial cells with or without H2S donor, GYY4137 and FOXO1 inhibitor, AS1842856 in HHcy condition and determined the involvement of Akt/FOXO1 signalling cascades. Our results indicated that Hcy inactivated Akt and activated FOXO1 by dephosphorylating both the signalling molecules and induced FOXO1 nuclear translocation followed by activation of the FOXO1 transcription factor. These led to the induction of cellular apoptosis and synthesis of excessive ECM protein, in part, due to increased ROS production, loss of mitochondrial membrane potential (ΔΨm), reduction in intracellular ATP concentration, increased MMP-2, -9, -14 mRNA and protein expression, and Col I, IV and fibronectin protein expression. Interestingly, GYY4137 or AS1842856 treatment prevented these changes by modulating Akt/FOXO1 axis in HHcy. We conclude that GYY4137 and/or AS1842856 mitigates HHcy induced mesangial cell damage and ECM remodelling by regulating Akt/FOXO1 pathway

Mitochondrial division/mitophagy inhibitor (Mdivi) Ameliorates Pressure Overload Induced Heart Failure

Background: We have previously reported the role of anti-angiogenic factors in inducing the transition from compensatory cardiac hypertrophy to heart failure and the significance of MMP-9 and TIMP-3 in promoting this process during pressure overload hemodynamic stress. Several studies reported the evidence of cardiac autophagy, involving removal of cellular organelles like mitochondria (mitophagy), peroxisomes etc., in the pathogenesis of heart failure. However, little is known regarding the therapeutic role of mitochondrial division inhibitor (Mdivi) in the pressure overload induced heart failure. We hypothesize that treatment with mitochondrial division inhibitor (Mdivi) inhibits abnormal mitophagy in a pressure overload heart and thus ameliorates heart failure condition. Materials and Methods: To verify this, ascending aortic banding was done in wild type mice to create pressure overload induced heart failure and then treated with Mdivi and compared with vehicle treated controls. Results: Expression of MMP-2, vascular endothelial growth factor, CD31, was increased, while expression of anti angiogenic factors like endostatin and angiostatin along with MMP-9, TIMP-3 was reduced in Mdivi treated AB 8 weeks mice compared to vehicle treated controls. Expression of mitophagy markers like LC3 and p62 was decreased in Mdivi treated mice compared to controls. Cardiac functional status assessed by echocardiography showed improvement and there is also a decrease in the deposition of fibrosis in Mdivi treated mice compared to controls

Synergism in hyperhomocysteinemia and diabetes: role of PPAR gamma and tempol

<p>Abstract</p> <p>Background</p> <p>Hyperhomocysteinemia (HHcy) and hyperglycemia cause diabetic cardiomyopathy by inducing oxidative stress and attenuating peroxisome proliferator- activated receptor (PPAR) gamma. However, their synergistic contribution is not clear.</p> <p>Methods</p> <p>Diabetic Akita (Ins2+/-) and hyperhomocysteinemic cystathionine beta synthase mutant (CBS+/-) were used for M-mode echocardiography at the age of four and twenty four weeks. The cardiac rings from WT, Akita and hybrid (Ins2+/-/CBS+/-) of Akita and CBS+/- were treated with different doses of acetylcholine (an endothelial dependent vasodilator). High performance liquid chromatography (HPLC) was performed for determining plasma homocysteine (Hcy) level in the above groups. Akita was treated with ciglitazone (CZ) - a PPAR gamma agonist and tempol-an anti-oxidant, separately and their effects on cardiac remodeling were assessed.</p> <p>Results</p> <p>At twenty four week, Akita mice were hyperglycemic and HHcy. They have increased end diastolic diameter (EDD). In their heart PPAR gamma, tissue inhibitor of metalloproteinase-4 (TIMP-4) and anti-oxidant thioredoxin were attenuated whereas matrix metalloproteinase (MMP)-9, TIMP-3 and NADPH oxidase 4 (NOX4) were induced. Interestingly, they showed synergism between HHcy and hyperglycemia for endothelial-myocyte (E-M) uncoupling. Additionally, treatment with CZ alleviated MMP-9 activity and fibrosis, and improved EDD. On the other hand, treatment with tempol reversed cardiac remodeling in part by restoring the expressions of TIMP-3,-4, thioredoxin and MMP-9.</p> <p>Conclusions</p> <p>Endogenous homocysteine exacerbates diabetic cardiomyopathy by attenuating PPAR gamma and inducing E-M uncoupling leading to diastolic dysfunction. PPAR gamma agonist and tempol mitigates oxidative stress and ameliorates diastolic dysfunction in diabetes.</p

Scenarios of cosmic string with variable cosmological constant

Exact solutions of the Einstein field equations with cosmic string and space varying cosmological constant, viz., $\Lambda= \Lambda(r)$, in the energy-momentum tensors are presented. Three cases have been studied: where variable cosmological constant (1) has power law dependence, (2) is proportional to the string fluid density, and (3) is purely a constant. Some cases of interesting physical consequences have been found out such that (i) variable cosmological constant can be represented by a power law of the type $\Lambda=3r^{-2}$, (ii) variable cosmological constant and cosmic string density are interdependent to each other according to the relation $\Lambda=-8\pi{\rho}_s$, and (iii) cosmic string density can be scaled by a power law of the type ${\rho}_s=r^{-2}$. It is also shown that several known solutions can be recovered from the general form of the solutions obtained here.Comment: 15 LaTeX pages; Two new sections (Secs 4 & 5) have been include

Total Aortic Arch Replacement: Superior Ventriculo-Arterial Coupling with Decellularized Allografts Compared with Conventional Prostheses.

BACKGROUND: To date, no experimental or clinical study provides detailed analysis of vascular impedance changes after total aortic arch replacement. This study investigated ventriculoarterial coupling and vascular impedance after replacement of the aortic arch with conventional prostheses vs. decellularized allografts. METHODS: After preparing decellularized aortic arch allografts, their mechanical, histological and biochemical properties were evaluated and compared to native aortic arches and conventional prostheses in vitro. In open-chest dogs, total aortic arch replacement was performed with conventional prostheses and compared to decellularized allografts (n = 5/group). Aortic flow and pressure were recorded continuously, left ventricular pressure-volume relations were measured by using a pressure-conductance catheter. From the hemodynamic variables end-systolic elastance (Ees), arterial elastance (Ea) and ventriculoarterial coupling were calculated. Characteristic impedance (Z) was assessed by Fourier analysis. RESULTS: While Ees did not differ between the groups and over time (4.1+/-1.19 vs. 4.58+/-1.39 mmHg/mL and 3.21+/-0.97 vs. 3.96+/-1.16 mmHg/mL), Ea showed a higher increase in the prosthesis group (4.01+/-0.67 vs. 6.18+/-0.20 mmHg/mL, P<0.05) in comparison to decellularized allografts (5.03+/-0.35 vs. 5.99+/-1.09 mmHg/mL). This led to impaired ventriculoarterial coupling in the prosthesis group, while it remained unchanged in the allograft group (62.5+/-50.9 vs. 3.9+/-23.4%). Z showed a strong increasing tendency in the prosthesis group and it was markedly higher after replacement when compared to decellularized allografts (44.6+/-8.3dyn.sec.cm-5 vs. 32.4+/-2.0dyn.sec.cm-5, P<0.05). CONCLUSIONS: Total aortic arch replacement leads to contractility-afterload mismatch by means of increased impedance and invert ventriculoarterial coupling ratio after implantation of conventional prostheses. Implantation of decellularized allografts preserves vascular impedance thereby improving ventriculoarterial mechanoenergetics after aortic arch replacement