Sexually dimorphic effects of SARM1 deletion on cardiac NAD+ metabolism and function.

Nicotinamide adenine dinucleotide (NAD+) decline is repeatedly observed in heart disease and its risk factors. Although strategies promoting NAD+ synthesis to elevate NAD+ levels improve cardiac function, whether inhibition of NAD+ consumption can be therapeutic is less investigated. In this study, we examined the role of sterile-α and TIR motif containing 1 (SARM1) NAD+ hydrolase in mouse hearts, using global SARM1-knockout mice (KO). Cardiac function was assessed by echocardiography in male and female KO mice and wild-type (WT) controls. Hearts were collected for biochemical, histological, and molecular analyses. We found that the cardiac NAD+ pool was elevated in female KO mice, but only trended to increase in male KO mice. SARM1 deletion induced changes to a greater number of NAD+ metabolism transcripts in male mice than in female mice. Body weights, cardiac systolic and diastolic function, and geometry showed no changes in both male and female KO mice compared with WT counterparts. Male KO mice showed a small, but significant, elevation in cardiac collagen levels compared with WT counterparts, but no difference in collagen levels was detected in female mice. The increased collagen levels were associated with greater number of altered profibrotic and senescence-associated inflammatory genes in male KO mice, but not in female KO mice.NEW & NOTEWORTHY We examined the effects of SARM1 deletion on NAD+ pool, transcripts of NAD+ metabolism, and fibrotic pathway for the first time in mouse hearts. We observed the sexually dimorphic effects of SARM1 deletion. How these sex-dependent effects influence the outcomes of SARM1 deficiency in male and female mice in responses to cardiac stresses warrant further investigation. The elevation of cardiac NAD+ pool by SARM1 deletion provides evidence that targeting SARM1 may reverse disease-related NAD+ decline.

Harnessing NAD+ Metabolism as Therapy for Cardiometabolic Diseases.

PURPOSE OF THE REVIEW: This review summarizes current understanding on the roles of nicotinamide adenine dinucleotide (NAD+) metabolism in the pathogeneses and treatment development of metabolic and cardiac diseases. RECENT FINDINGS: NAD+ was identified as a redox cofactor in metabolism and a co-substrate for a wide range of NAD+-dependent enzymes. NAD+ redox imbalance and depletion are associated with many pathologies where metabolism plays a key role, for example cardiometabolic diseases. This review is to delineate the current knowledge about harnessing NAD+ metabolism as potential therapy for cardiometabolic diseases. The review has summarized how NAD+ redox imbalance and depletion contribute to the pathogeneses of cardiometabolic diseases. Therapeutic evidence involving activation of NAD+ synthesis in pre-clinical and clinical studies was discussed. While activation of NAD+ synthesis shows great promise for therapy, the field of NAD+ metabolism is rapidly evolving. Therefore, it is expected that new mechanisms will be discovered as therapeutic targets for cardiometabolic diseases.

Activation of toll like receptor 4 (TLR4) promotes cardiomyocyte apoptosis through SIRT2 dependent p53 deacetylation.

Cardiomyocyte inflammation followed by apoptosis and fibrosis is an important mediator for development and progression of heart failure. Activation of toll-like receptor 4 (TLR4), an important regulator of inflammation, causes the progression of cardiac hypertrophy and injury. However, the precise mechanism of TLR4-mediated adverse cardiac outcomes is still elusive. The present study was designed to find the role of TLR4 in cardiac fibrosis and apoptosis, and molecular mechanism thereof. Rats were treated with TLR4 agonist (LPS 12.5 µg/kg/day) through osmotic pump for 14 days. To simulate the condition in vitro, H9c2 cells were treated with LPS (1 µg/ml). Similarly, H9c2 cells were transfected with TLR4 and SIRT2 c-DNA clone for overexpression. Myocardial oxidative stress, inflammation, fibrosis and mitochondrial parameters were evaluated both in vitro and in vivo. Cardiac inflammation after LPS treatment was confirmed by increased TNF-α and IL-6 expression in rat heart. There was a marked increase in oxidative stress as observed by increased TBARS and decreased endogenous antioxidants (GSH and catalase), along with mitochondrial dysfunction as measured by mitochondrial complex activity in LPS-treated rat hearts. Histopathological examination showed the presence of cardiac fibrosis after LPS treatment. Protein expression of nuclear p53 and cleaved caspase-7/caspase-9 was significantly increased in LPS treated heart. Similar to in vivo study, nuclear translocation of p53, mitochondrial dysfunction and cellular apoptosis were observed in H9c2 cells treated with LPS. Our data also indicate that decreased expression of SIRT2 was associated with increased acetylation of p53 after LPS treatment. In conclusion, TLR4 activation in rats promotes cardiac inflammation, mitochondrial dysfunction, apoptosis and fibrosis. p53 and caspase 7/caspase 9 were found to play an important role in TLR4-mediated apoptosis. Our data suggest that, reducing TLR4 mediated fibrosis and apoptosis could be a novel approach in the treatment of heart failure, keeping in the view the major role played by TLR4 in cardiac inflammation.

Vitamin D Deficiency in Rats Causes Cardiac Dysfunction by Inducing Myocardial Insulin Resistance.

SCOPE: Cause-effect relationship between vitamin D deficiency and cardiometabolic abnormalities remains undefined. The aim is to investigate the role of vitamin D deficiency in cardiac failure, through possible involvement in myocardial insulin signaling. METHODS AND RESULTS: Male SD rats (n = 6) are fed a normal diet (Con), vitamin D-deficient diet [Con(-)], or high-fat, high fructose diet (HFHFrD) for 20 weeks. Cardiac hypertrophy and fetal gene program are confirmed in Con(-) group. Cardiac dysfunction is assessed by echocardiography. Elevated renin, TGF-ß and collagen-1α mRNAs, p-ERK1/2, and perivascular fibrosis indicate cardiac remodeling in Con(-) group. Increased serum insulin, triglycerides, and blood pressure, and decreased glucose tolerance and HDL cholesterol are observed in Con(-) rats. Decreased p-Akt/Akt, GLUT4, SOD2, and catalase, and increased NF-κB, TNF-α, and IL-6 are observed in Con(-) hearts. In H9c2 cells, calcitriol attenuates palmitate-induced insulin resistance. VDR-silenced H9c2 cells show reduced Akt phosphorylation, GLUT4 translocation, and 2-NBDG uptake. Findings in Con(-) and HFHFrD groups are comparable. CONCLUSION: Vitamin D deficiency in rats mimic high-fat-, high-fructose-induced metabolic syndrome and cardiac dysfunction. This study demonstrates that vitamin D deficiency is an independent risk factor for heart failure, at least in part, through induction of myocardial insulin resistance.